**Figure 2.** ( **A** ) Overlap of crizotinib extracted from complexes with
c-Met (yellow), ALK (magenta), and ROS1 (orange). Two-dimensional
representation of first-generation inhibitors, ( **B** ) crizotinib and (
**C** ) lorlatinib, with the following color scheme for the atoms: carbon
(grey), oxygen (red), nitrogen (blue), chlorine (green), and fluorine (cyan).
The interactions were analyzed and plotted using Discovery Studio Visualizer
and Pymol.


  * [ Discussions ](https://github.com/orgs/foxglove/discussions)
  * [ Slack ](/slack)
  * [ Twitter ](https://twitter.com/foxglove)


      void objectCallback(){
        // All transforms must be correctly time-stamped
        pose_.header.stamp = ros::Time::now();
        pose_.header.frame_id = "sensor_link";

        if (count_ % 2) {
          pose_.pose.position.x = 1.0;
          pose_.pose.position.y = 1.0;
        } else {
          pose_.pose.position.x = 2.0;
          pose_.pose.position.y = 3.0;
        }

        // Change the detected object’s position, depending on whether count_ is even or odd
        count_++;
        pose_pub_.publish(pose_);
      }


Juliana F. Vilachã holds a Bachelor of Science degree in Pharmaceutical
Sciences from the Federal University of Rio de Janeiro, Brazil, and a Master
of Science degree in Medical and Pharmaceutical Drug Innovation from the
University of Groningen, The Netherlands. Her research focuses on biomolecular
processes, particularly protein mutation and drug resistance, with a major
emphasis on cancer and kinases. Currently, she is a Ph.D. candidate at the
Molecular Dynamics Group at the University of Groningen, The Netherlands.


Open a connection to your data in Foxglove Studio using the [ Foxglove bridge
](/blog/announcing-the-new-foxglove-bridge-for-live-ros-data) . Open a [ 3D
panel ](https://docs.foxglove.dev/docs/visualization/panels/3d) to visualize
the frames and detected object positions, and a [ Log panel
](https://docs.foxglove.dev/docs/visualization/panels/log) to see the printout
of our object’s position.


Next, write a class constructor that publishes the detected object’s pose on a
timer (every second). Since poses are not transform messages, they will be
published on a ` /detected_object ` topic (instead of ` /tf ` or ` /tf_static
` ):


Note that from the first issue of 2016, this journal uses article numbers
instead of page numbers. See further details [ here
](https://www.mdpi.com/about/announcements/784) .


The major difference between all crystal structures concerns the pyrazole
ring; while positioned between two key residues, L1951 and G2032 (ROS1), it
retains a level of rotational freedom. Thus, the rotation of the pyrazole ring
is associated with the piperidine ring’s position. The conformation observed
for the pyrazole ring in the ROS1 complex is comparable to the position for
the same drug on the ALK receptor (PDB: ID 2XP2), another target for this
small molecule. The difference observed for c-MET can be credited to the
presence of tyrosine (Y1159) in the place of leucine as observed for ALK and
ROS1 (L1198 and L2028, respectively) (  Figure 2  ). The behavior of this
five-member ring might affect the binding, as interactions with the G-loop are
pivotal for drug binding in type I inhibitors such as crizotinib [  16  ]. In
addition, molecular electrostatic potential (MEP) calculations show a
concentration of negative charges around the pyrazole and pyridine rings and
positive charges in the substituted benzene ring, which could explain the
structure–activity relationship of crizotinib and cMET, ALK, and ROS1 targets
[  17  ].


    $ rosrun tf2_ros static_transform_publisher 1 1 0 0 0 0 base_link arm_base_link
    $ rosrun tf2_ros static_transform_publisher 1 -1 0 0 0 0 base_link sensor_link


Vilachã, J.F.; Wassenaar, T.A.; Marrink, S.J. Structural Aspects of the ROS1
Kinase Domain and Oncogenic Mutations. _Crystals_ **2024** , _14_ , 106.
https://doi.org/10.3390/cryst14020106


##  Share and Cite


Gatekeeper residues are in the hinge motif’s N-terminal end and are
responsible for the accessibility to the “back pocket” of kinases. Gatekeeper
mutations are the most common resistance mutation to kinase inhibitors and
have been described for many different kinases [  28  ]. In ROS1, the
gatekeeper residue is L2026, and the most common mutation is the change of
leucine into methionine (  Figure 6  ) [  29  ].


__ __ __


Open Access  Feature Paper  Review


Notice that the object arrow is different from the axes arrows that represent
each frame. This is because the object is not a transform, but a [ ` Pose `
](http://docs.ros.org/en/noetic/api/geometry_msgs/html/msg/PoseStamped.html) .
If you use the [ Teleop panel
](https://docs.foxglove.dev/docs/visualization/panels/teleop) to move the `
arm_end_link ` frame around, you can see firsthand how the position of your
detected object changes.


##  4\. Conclusions


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Read more about our cookies [ here ](/about/privacy) .


Define a ` TfListener ` class with the following private variables:


In previous posts, we've covered how [ visualizing ROS 1 transforms in
Foxglove Studio ](/blog/publishing-and-visualizing-ros1-transforms) can help
us [ describe the relative positions of a robot’s components
](/blog/understanding-ros-transforms) .


Page


Multiple requests from the same IP address are counted as one view.


![](/bundles/mdpisciprofileslink/img/unknown-user.png) Siewert J. Marrink


In the same study, using funnel-based well-tempered metadynamics and umbrella
sampling to calculate the absolute binding free energy of crizotinib, it was
possible to support the correlation between the P-loop rigidity and the effect
on the drug binding. The results show that the G2032R mutants sustain a more
open conformation of the G-loop, impacting the interaction between the L1951
residue and the drug. This residue in the ROS1  WT  complex and crizotinib was
responsible for the highest contribution to drug binding [  32  ]. Another
study using MD simulations of the apo WT and ROS1  G2032R  supports the
overall protein rigidity found in the mutant, especially for the G-loop and
the A-loop. The different mobility observed between native and mutant ROS1 was
credited to the loss and gain of intramolecular interactions. A stabilizing
salt bridge was identified between the guanidinium group of R2032 and the
carboxyl in the E1961 in the mutant. Meanwhile, the stabilizing hydrogen bond
between E1961 and R1948 identified in the apo ROS1  WT  simulations was lost
in the presence of this mutation. This study showed that not only mutation of
the glycine to an arginine leads to steric hindrance of crizotinib binding,
but also how the G2032R mutation modifies the intramolecular interactions in
the kinase domain that could account for drug resistance [  4  ].


[ ![Foxglove](/images/logo-white.svg) ](/)


##  list_controllers  


#  Using ROS 1 Transforms to Calculate Object Positions


Figure 1

\(A\) Schematic representation of active ROS1 kinase domain with crizotinib \(PDB: ID 3ZBF\). Mutation hotspots, indicated in red \(L2026\) and blue \(G2032\), are depicted as spheres. \(B\) The zoomed-in region shows the hydrophobic cluster involving residues L2000, F2004, F2103, A2106, and F2075.

                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g002.png?1705989466 "
                        Figure 2

\(A\) Overlap of crizotinib extracted from complexes with c-Met \(yellow\), ALK \(magenta\), and ROS1 \(orange\). Two-dimensional representation of first-generation inhibitors, \(B\) crizotinib and \(C\) lorlatinib, with the following color scheme for the atoms: carbon \(grey\), oxygen \(red\), nitrogen \(blue\), chlorine \(green\), and fluorine \(cyan\). The interactions were analyzed and plotted using Discovery Studio Visualizer and Pymol.

                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g003.png?1705989467 "
                        Figure 3

Two-dimensional representations of inhibitor prototypes, \(A\) compound 1 \(PDB: ID 7Z5X\) and \(B\) compound 2 \(PDB: ID 7Z5W\), with the following color scheme for the atoms: carbon \(grey\), oxygen \(red\), nitrogen \(blue\), sulfur \(yellow\), and fluorine \(cyan\). Interactions were analyzed and plotted using Discovery Studio Visualizer.

                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g004.png?1705989469 "
                        Figure 4

Interaction map for \(A\) entrectinib in the ROS1 active conformation proposed by Menichincheri et al. \[24\], and \(B\) cabozantinib and \(C\) foretinib in the inactive conformation proposed by Davare et al. \[4\].

                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g005.png?1705989471 "
                        Figure 5

\(A\) Superposition of the active \(green\) experimentally determined \(PDB: ID 3ZBF\) and the inactive model \(purple\) obtained through homology modeling \(template PDB: ID 4FNY\). \(B\) The residue F2103 side chain from the DFG motif is represented as a stick in the active structure \(green\) and the inactive model \(purple\).

                                                ") [ ](https://pub.mdpi-res.com/crystals/crystals-14-00106/article_deploy/html/images/crystals-14-00106-g006.png?1705989472 "
                        Figure 6

Representation of point mutations in the ROS1 kinase domain: \(A\) L2026M, \(B\) G2032R, and \(C\) D2033N. In all figures, the native ROS1 is represented in green with the mutated residues represented in yellow, while being superimposed with the native counter partner residue. Key structural motifs such as the G-loop and the <math display="inline"><semantics>
  <mi>α</mi>


►  ▼  Article Menu


    $ ros2 control set_hardware_component_state -h
    usage: ros2 control set_hardware_component_state [-h] [--spin-time SPIN_TIME] [-s] [-c CONTROLLER_MANAGER] [--include-hidden-nodes]
                                                    hardware_component_name {unconfigured,inactive,active}

    Adjust the state of the hardware component

    positional arguments:
      hardware_component_name
                            Name of the hardware_component to be changed
      {unconfigured,inactive,active}
                            State in which the hardware component should be changed to

    options:
      -h, --help            show this help message and exit
      --spin-time SPIN_TIME
                            Spin time in seconds to wait for discovery (only applies when not using an already running daemon)
      -s, --use-sim-time    Enable ROS simulation time
      -c CONTROLLER_MANAGER, --controller-manager CONTROLLER_MANAGER
                            Name of the controller manager ROS node
      --include-hidden-nodes
                            Consider hidden nodes as well


. **
#  position_controllers  
This is a collection of controllers that work using the “position” joint
command interface but may accept different joint-level commands at the
controller level, e.g. controlling the position on a certain joint to achieve
a set velocity.
The package contains the following controllers:
##  position_controllers/JointGroupPositionController  
This is specialization of the [ forward_command_controller
](../../forward_command_controller/doc/userdoc.html#forward-command-
controller-userdoc) that works using the “position” joint interface.
###  ROS 2 interface of the controller  
####  Topics  
~/commands (input topic) [std_msgs::msg::Float64MultiArray]

Joints’ position commands
####  Parameters  
This controller overrides the interface parameter from [
forward_command_controller
](../../forward_command_controller/doc/userdoc.html#forward-command-
controller-userdoc) , and the ` joints  ` parameter is the only one that is
required.
An example parameter file is given here

    controller_manager:
      ros__parameters:
        update_rate: 100  # Hz

        position_controller:
          type: position_controllers/JointGroupPositionController

    position_controller:
      ros__parameters:
        joints:
          - slider_to_cart

[ Previous ](../../pid_controller/doc/userdoc.html "PID Controller") [ Next
](../../velocity_controllers/doc/userdoc.html "velocity_controllers")
* * *


</semantics></math>C-helix are highlighted in the figures to aid
identification of their location.</p>


Example output:


Advanced  Search


The same study also proposed a binding pose for foretinib, a potent ROS1
inhibitor structurally related to cabozantinib [  7  ]. The predominant pose
obtained from the RCS approach using the apo MD simulations is like the one
proposed for cabozantinib with the additional morpholine ring interacting with
the K1967 and E2030 residues. A closely related binding conformation was also
observed for the same molecule, but with the cMET receptor (PDB: ID 6SD9) [
27  ]. However, a minor cluster of poses obtained from the docking study
demonstrated a reversed position of the drug in the binding pocket, with the
morpholine closer to the  α  C-helix. This alternative binding mode highlights
a second interaction mode and this may be reason why this mutation retains
sensitivity to foretinib even when cabozantinib does not [  4  ].


![](/bundles/mdpisciprofileslink/img/unknown-user.png) Juliana F. Vilachã


>   * ros2 control list_controllers
>
>   * ros2 control list_controller_types
>
>   * ros2 control list_hardware_components
>
>   * ros2 control list_hardware_interfaces
>
>   * ros2 control load_controller
>
>   * ros2 control reload_controller_libraries
>
>   * ros2 control set_controller_state
>
>   * ros2 control set_hardware_component_state
>
>   * ros2 control switch_controllers
>
>   * ros2 control unload_controller
>
>   * ros2 control view_controller_chains
>
>


##  Notice


###  Product


_Crystals_ **2024** , _14_ (2), 106; [ https://doi.org/10.3390/cryst14020106
](https://doi.org/10.3390/cryst14020106)


  * [ Download ](/download)
  * [ Documentation ](/docs)
  * [ Tutorials ](/tutorials)
  * [ ROS visualization ](/ros)
  * [ Rosbridge ](/rosbridge)
  * [ URDF visualization ](/urdf)


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    public:
      TfListener():
      NodeHandle("~") {
        // Listen to the buffer of transforms
        tf_listener_ = new tf2_ros::TransformListener(tf_buffer_);
        // Subscribe to pose published by sensor node (check every second)
        pose_sub_ = subscribe<geometry_msgs::PoseStamped>
          ("/detected_object", 10, &TfListener::poseCallback, this);
      }

      ~TfListener(){}
    };


[ Move It Octomap not working ](/question/413695/move-it-octomap-not-working/)


[ LinkedIn ](https://www.linkedin.com/company/mdpi) [ Facebook
](https://www.facebook.com/MDPIOpenAccessPublishing) [ Twitter
](https://twitter.com/MDPIOpenAccess)


Supporting these findings, MMPBSA calculations showed a decrease in the
enthalpic term of free energy calculations. This decrease was especially
associated with E2027 and M2029 residues, both involved in hydrogen bonds with
the aminopyridine scaffold [  29  ]. Since ROS1 G2032R was proved to be
resistant to crizotinib, it was necessary to seek new molecular entities able
to inhibit this variant.


[ ![](/bundles/mdpisciprofileslink/img/unknown-user.png) Houfu Guo
](https://sciprofiles.com/profile/2514922?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)


[ Review Reports ](/2073-4352/14/2/106/review_report) [ Versions Notes
](/2073-4352/14/2/106/notes)


Experience Foxglove’s data storage and collaboration features for 14 days


#  Command Line Interface  


Vilachã, J.F.; Wassenaar, T.A.; Marrink, S.J. Structural Aspects of the ROS1
Kinase Domain and Oncogenic Mutations. _Crystals_ **2024** , _14_ , 106.
https://doi.org/10.3390/cryst14020106


Follow


      * [ Vilachã, J. F. ](https://scholar.google.com/scholar?q=Juliana%20F.%20Vilach%C3%A3)
      *       * [ Wassenaar, T. A. ](https://scholar.google.com/scholar?q=Tsjerk%20A.%20Wassenaar)
      *       * [ Marrink, S. J. ](https://scholar.google.com/scholar?q=Siewert%20J.%20Marrink)
      *     * on PubMed


Lastly, write a ` main ` function that declares and spins the node:


**Figure 4.** Interaction map for ( **A** ) entrectinib in the ROS1 active
conformation proposed by Menichincheri et al. [  24  ], and ( **B** )
cabozantinib and ( **C** ) foretinib in the inactive conformation proposed by
Davare et al. [  4  ].


article


[ Issue 2 ](/2073-4352/14/2)


[ **asked 2022-07-01 10:21:39 -0500  ** ](/questions/403250/revisions/)


Additional point mutations have been described for ROS1, but often with
different fusion partners. A more extensive description of single mutations
and their associated fusion partners can be read in other papers [  37  ,  38
]. It is interesting to highlight that most in silico studies focus on the
classical G2032R and L206M, thus leaving a gap for other mutations and their
impact in the ROS1 kinase domain and further mechanisms of resistance.


](/authors/english)


##  Author Contributions


    #include <ros/ros.h>
    #include "geometry_msgs/PoseStamped.h"
    #include "tf2_geometry_msgs/tf2_geometry_msgs.h"
    #include "tf2/exceptions.h"
    #include "tf2_ros/transform_listener.h"
    #include "tf2_ros/buffer.h"


edit


Published  March 20, 2023


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##  2\. The Native ROS1 Kinase Domain


The Protein Data Bank (PDB) contains, to this day, only four available
structures of the ROS1 kinase domain (PDB: IDs 3ZBF, 4UXL, 7Z5W, 7Z5X), and
all obtained through X-ray crystallography and co-crystallized with different
ligands [  5  ,  6  ,  12  ]. From these ligands, the multikinase inhibitor
crizotinib was initially designed to inhibit the hepatocyte growth factor
receptor (HGFR or c-MET) and later had its application extended to ALK and
ROS1. When comparing crizotinib complexes with ALK (PDB: ID 2XP2), ROS1 (PDB:
ID 3ZBF), and c-MET (PDB: ID 2WGJ), it is possible to observe a fair overlap
of this small molecule in all structures. The drug binds to the ATP binding
pocket in all proteins similarly, the 2-amino-pyridine ring engages in two
hydrogen bonds with the backbone hinge residues, in the case of ROS1 being
E2027 and M2029. Due to the R configuration, the methoxy unit containing the
chiral carbon guides the 2,6-dichloro-3-fluorophenyl ring towards the DFG
motif at the beginning of the activation loop (  Figure 2  ) [  5  ,  6  ,  12
].


[ none ](/questions/scope:all/sort:activity-desc/tags:none/page:1/) ×


###  Feedback


Other ALK inhibitors also showed effective inhibition of ROS1. Entrectinib, a
3-aminoindazole derivative, was initially designed as a type I ALK inhibitor
(IC  50  = 12 nM), with a comparable sensitivity to ROS1 (IC  50  = 7 nM) [
24  ]. Although a crystal structure of ALK in complex with entrectinib was
resolved and is available (PDB: ID 5FTO), a crystal structure of the complex
between ROS1 and this small molecule is not available at this moment. However,
a study using MD simulations and Molecular Mechanics Poisson–Boltzmann Surface
Area (MMPBSA) calculations proposes a mechanism for the binding profile of
entrectinib. Overall, the binding affinities obtained from MMPBSA calculations
of this drug to ALK and ROS1 are comparable (−40.92 ± 0.32 and −36.60 ± 0.38
kcal/mol, respectively) and both rely on similar residues within the ATP
binding pocket, with a major contribution of the L2026 residue [  25  ]. In
addition, the major role of L2086 is featured in the stabilization of the
ROS1–entrectinib complex due to its consistent interaction with the
3,5-difluoro benzyl ring (  Figure 4  ) [  24  ].


Despite the success of crizotinib, there is a limitation in its ability to
cross the blood–brain barrier and tackle metastatic incidences of ROS1+ tumors
in the brain. As such, crizotinib was modified using a structure-based drug
design (SBDD) approach, leading to a macrocyclic final product: lorlatinib.
This macrocycle showed a lower propensity for p-glycoprotein (P-gp) efflux and
improved blood–brain barrier (BBB) penetration [  18  ]. The design of
lorlatinib conserved the hinge-binding amino pyridine scaffold and the chiral
center. The fluoro substituent on the aromatic ring was conserved, while the
two chlorines were not. The pyrazole ring was N-methylated and substituted at
position 3 with a carbonitrile group. The pyrazole ring and the fluoro-phenyl
ring were then connected by a methyl-amide motif, leading to the cyclization
of the structure [  18  ,  19  ].


Next Article in Journal


The site is read-only. Please transition to use Robotics Stack Exchange


In the same study, cabozantinib, an analog to foretinib, showed effective
inhibition of the CD74-ROS1  G2032R  cell line. The docking of cabozantinib in
the ensemble of either the native or the mutated ROS1 was considered favorable
and mirrored the in vitro assessment [  4  ]. Despite the limited data, the
aforementioned description of a probable foretinib binding mode to ROS1 can
explain the sustained sensitivity of the G2032R mutant to this type II
inhibitor [  7  ].


####  3.5. Additional Single and Double Mutations


Copy


One of the novel structures shows the binding of an insulin-like growth factor
receptor (IGR-1R) inhibitor (ligand 1) to the ROS1 kinase domain (PDB: ID
7Z5W). In this crystallized structure, the hinge binding motif is the
2-aminothiazole group that engages in two hydrogen bonds with the backbone of
M2029 through both nitrogen atoms, the aromatic one acting as an acceptor and
the other as a donor. Another hydrogen bond is mediated by a water molecule
between the pyrimidine group and the side chain of D2033. The pyrimidine ring
from ligand 1 is also positioned between residues L1951 and G2032, comparable
to the pyrazole ring in crizotinib. The isoxazole and pyrrolidine rings
contribute as linkers to guide the 3-methyl pyrazine ring toward the beginning
of the activation loop. In one of the monomers that composes the crystal
structure, it is possible to identify an interaction of this motif with the
side chain of the D2102 in the DFG motif (  Figure 3  ) [  12  ].


Finally, run your new nodes:


_clear_ [ _zoom_out_map_ ](/toggle_desktop_layout_cookie "Toggle desktop
layout") _search_ _menu_


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![example robot model](/images/blog/using-ros1-transforms-to-calculate-object-
positions/robot.png)


[ ROS1 ](/search?q=ROS1) ; [ kinase inhibitor ](/search?q=kinase+inhibitor) ;
[ X-ray crystallography ](/search?q=X-ray+crystallography) ; [ molecular
modeling ](/search?q=molecular+modeling)


Submission received: 11 December 2023  /  Revised: 11 January 2024  /
Accepted: 18 January 2024  /  Published: 23 January 2024


Read more  Read less


First time here? Check out the FAQ!


##  Calculating positions in different frames


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[ __ Download PDF ](/2073-4352/14/2/106/pdf?version=1705989379)


Example output:


Vilachã, Juliana F., Tsjerk A. Wassenaar, and Siewert J. Marrink. 2024\.
"Structural Aspects of the ROS1 Kinase Domain and Oncogenic Mutations"
_Crystals_ 14, no. 2: 106. https://doi.org/10.3390/cryst14020106


Next, write a class constructor that loads and listens to your buffer of
transforms, and then subscribe’s to the sensor’s ` /detected_object ` pose
topic:


Section


    $ ros2 control switch_controllers -h
    usage: ros2 control switch_controllers [-h] [--spin-time SPIN_TIME] [--deactivate [CTRL1 [CTRL2 ...]]] [--activate [CTRL1 [CTRL2 ...]]] [--strict] [--activate-asap] [--switch-timeout SWITCH_TIMEOUT] [-c CONTROLLER_MANAGER]
                                          [--include-hidden-nodes]

    Switch controllers in a controller manager

    optional arguments:
    -h, --help            show this help message and exit
    --spin-time SPIN_TIME
    Spin time in seconds to wait for discovery (only applies when not using an already running daemon)
    --deactivate [CTRL1 [CTRL2 ...]]
    Name of the controllers to be deactivate
    --activate [CTRL1 [CTRL2 ...]]
    Name of the controllers to be activated
    --strict              Strict switch
    --activate-asap       Activate asap controllers
    --switch-timeout SWITCH_TIMEOUT
    Timeout for switching controllers
    -c CONTROLLER_MANAGER, --controller-manager CONTROLLER_MANAGER
    Name of the controller manager ROS node
    --include-hidden-nodes
                          Consider hidden nodes as well


[ getCurrentPose take too long time ](/question/359342/getcurrentpose-take-
too-long-time/)


(This article belongs to the Special Issue [ Crystallography of Enzymes ](
    /journal/crystals/special_issues/V31QQJ71YR
) )


**Figure 6.** Representation of point mutations in the ROS1 kinase domain: (
**A** ) L2026M, ( **B** ) G2032R, and ( **C** ) D2033N. In all figures, the
native ROS1 is represented in green with the mutated residues represented in
yellow, while being superimposed with the native counter partner residue. Key
structural motifs such as the G-loop and the  α  C-helix are highlighted in
the figures to aid identification of their location.


##  load_controller  


#  Structural Aspects of the ROS1 Kinase Domain and Oncogenic Mutations


**Figure 5.** ( **A** ) Superposition of the active (green) experimentally
determined (PDB: ID 3ZBF) and the inactive model (purple) obtained through
homology modeling (template PDB: ID 4FNY). ( **B** ) The residue F2103 side
chain from the DFG motif is represented as a stick in the active structure
(green) and the inactive model (purple).


##  list_controller_types  


Protein kinases function as pivotal regulators in biological events, governing
essential cellular processes through the transfer of phosphate groups from ATP
molecules to substrates. Dysregulation of kinase activity is frequently
associated with cancer, ocasionally arising from chromosomal translocation
events that relocate genes encoding kinases. Fusion proteins resulting from
such events, particularly those involving the proto-oncogene tyrosine-protein
kinase ROS (ROS1), manifest as constitutively active kinases, emphasizing
their role in oncogenesis. Notably, the chromosomal reallocation of the ros1
gene leads to fusion of proteins with the ROS1 kinase domain, implicated in
various cancer types. Despite their prevalence, targeted inhibition of these
fusion proteins relies on repurposed kinase inhibitors. This review
comprehensively surveys experimentally determined ROS1 structures, emphasizing
the pivotal role of X-ray crystallography in providing high-quality insights.
We delve into the intricate interactions between ROS1 and kinase inhibitors,
shedding light on the structural basis for inhibition. Additionally, we
explore point mutations identified in patients, employing molecular modeling
to elucidate their structural impact on the ROS1 kinase domain. By integrating
structural insights with in vitro and in silico data, this review advances our
understanding of ROS1 kinase in cancer, offering potential avenues for
targeted therapeutic strategies.


##  list_hardware_components  


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###  Article Access Statistics


If our robot’s sensor were to detect an object, we'd have that object’s
position in the ` sensor_link ` frame. To use our robot’s arm to grab it,
however, we’d then need to calculate the object’s position in the `
arm_end_link ` frame.


It should also include a timer callback, to periodically publish the detected
object’s position:


    add_executable(sensor src/sensor.cpp)
    add_executable(tf_listener src/tf_listener.cpp)

    target_link_libraries(sensor
      ${catkin_LIBRARIES}
    )
    target_link_libraries(tf_listener
      ${catkin_LIBRARIES}
    )


[ UM7 - Unable to set CREG_COM_SETTINGS ](/question/303494/um7-unable-to-set-
creg_com_settings/)


As observed for the ALK fusions, the treatment of crizotinib in ROS1-positive
patients also led to a rise in point mutations in the kinase domain. The first
mutation detected was in a lung cancer patient initially treated with
crizotinib in a residue exposed to the solvent. The authors reported the
G2032R mutation as resistant to crizotinib (  Figure 6  ) [  5  ]. This
mutation is analogous to the G1202R ALK mutation that is also linked to
crizotinib resistance (  Figure 6  ) [  30  ,  31  ].


© Copyright 2024, ros2_control Development Team.


The fusion product conserves the ROS1 kinase domain, which follows the
conserved folding previously mentioned: a bilobal protein with the N- and
C-terminal lobes connected by a hinge. As observed from the first ever
determined crystal structure of the ROS1 kinase domain, the N-terminal
contains a regulatory  α  C-helix and a  β  -sheet composed of four strands.
The  α  C-helix is connected to the  β  3 and  β  4 strands. The  β  1 and  β
2 strands are connected through the G-loop, which acts as the lid of the ATP
binding pocket [  5  ]. In the active conformation, the activation loop, a
polypeptide region of the C-terminal lobe with increased structural
flexibility, is presented in an extended manner with the conserved Aspartic
acid–Phenylalanine–Glycine (DFG) motif at its beginning. Once the protein
assumes a DFG-in conformation, the DFG phenylalanine side chain is guided into
a hydrophobic pocket and engages in hydrophobic stacking interactions [  15
]. This pocket, explored by Davares et al., contains residues from the  α
C-helix (L2000 and F2004), the DFG motif (F2103), and the other aromatic
residues from the C-terminal (A2106 and F2075). A homologous pocket is
observed on the ALK-active conformation and is reported to contribute to the
maintenance of the active state [  4  ] (  Figure 1  ).


* [ moveit ](/questions/scope:all/sort:activity-desc/tags:moveit/page:1/)


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Juliana F. Vilachã


Search Type


[ RViz Crashing (Ogre or MoveIt!) ](/question/312646/rviz-crashing-ogre-or-
moveit/)


Browse Figures


article


Note that from the first issue of 2016, this journal uses article numbers
instead of page numbers. See further details [ here
](https://www.mdpi.com/about/announcements/784) .


[ Give Feedback ](/feedback/send)


**Figure 4.** Interaction map for ( **A** ) entrectinib in the ROS1 active
conformation proposed by Menichincheri et al. [  24  ], and ( **B** )
cabozantinib and ( **C** ) foretinib in the inactive conformation proposed by
Davare et al. [  4  ].


Read more  Read less


[ edit ](/questions/403250/edit/) [ retag ](/s/questions/403250/retag/) flag
offensive  [ close ](/questions/403250/close/) merge  delete


    $ ros2 control list_controller_types
    diff_drive_controller/DiffDriveController                              controller_interface::ControllerInterface
    joint_state_broadcaster/JointStateBroadcaster                          controller_interface::ControllerInterface
    joint_trajectory_controller/JointTrajectoryController                  controller_interface::ControllerInterface


Siewert J. Marrink


##  Author Services


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](http://discourse.ros.org/) | [ Index ](http://index.ros.org/) | [ Service
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](https://robotics.stackexchange.com/questions/tagged/ros)
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###  Create a listener node to calculate the object’s position


##  Article Menu


The aspartic acid at position 2033 is located at the C-terminal of the hinge (
Figure 6  ). ROS1  D2033N  was initially found in a patient with resistance to
crizotinib, which was later confirmed through Ba/F3 cells expressing CD74-ROS1
D2033N  [  34  ]. Cabozantinib was then administered to the patient, who
presented a positive response. The combination of MD simulations and docking
studies highlighted the strong electrostatic interaction between the
piperidine ring of crizotinib and the negatively charged side chain of D2033.
However, the mutant lacks this interaction, as the inserted asparagine lacks
the negatively charged side chain. Instead, the N2033 side chain reorients
towards the G-loop and engages in a water-mediated hydrogen bond with L1951,
leading to a slight loss in flexibility in the G-loop [  34  ].


**Figure 7.** Representation of the kinase domain and single mutations. The
side chain of native residues with identified mutations is colored in purple
and depicted as spheres.


In cancer, protein kinases can be activated by mutations in nucleotides, the
gain or loss of chromosomes (somatic mutations or chromosomal alterations),
and gene amplification [  1  ]. The discovery of the echinoderm microtubule-
associated protein-like 4 (EML4) and the Anaplastic Lymphoma Kinase (ALK)
fusion protein as a druggable target was a benchmark for treating lung
adenocarcinomas [  2  ]. This finding highlights the importance of identifying
and inhibiting such proteins to successfully treat a subset of non-small cell
lung cancer (NSCLC). Later, the proto-oncogene tyrosine-protein kinase ROS
(ROS1) (UniProt ID: P08922), an orphan receptor tyrosine kinase, was
associated with tumorigenesis and identified in an NSCLC patient with tumor
progression. Like ALK, ROS1 can be fused with different partners, the most
common being the cell-surface receptor cluster differentiation (CD) 74 [  3
].


    $ ros2 control list_controller_types -h
    usage: ros2 control list_controller_types [-h] [--spin-time SPIN_TIME] [-c CONTROLLER_MANAGER] [--include-hidden-nodes]

    Output the available controller types and their base classes

    optional arguments:
      -h, --help            show this help message and exit
      --spin-time SPIN_TIME
                            Spin time in seconds to wait for discovery (only applies when not using an already running daemon)
      -c CONTROLLER_MANAGER, --controller-manager CONTROLLER_MANAGER
                            Name of the controller manager ROS node
      --include-hidden-nodes
                            Consider hidden nodes as well


[ Master ](userdoc.html)


    $ ros2 control list_controllers -h
    usage: ros2 control list_controllers [-h] [--spin-time SPIN_TIME] [-c CONTROLLER_MANAGER] [--include-hidden-nodes]

    Output the list of loaded controllers, their type and status

    optional arguments:
      -h, --help            show this help message and exit
      --spin-time SPIN_TIME
                            Spin time in seconds to wait for discovery (only applies when not using an already running daemon)
      -c CONTROLLER_MANAGER, --controller-manager CONTROLLER_MANAGER
                            Name of the controller manager ROS node
      --include-hidden-nodes
                            Consider hidden nodes as well


[ Get started for free ](https://app.foxglove.dev/signup)


    $ ros2 control view_controller_chains -h
    usage: ros2 view_controller_chains

    Generates a diagram of the loaded chained controllers into /tmp/controller_diagram.gv.pdf

    options:
      -h, --help            show this help message and exit
      --spin-time SPIN_TIME
                            Spin time in seconds to wait for discovery (only applies when not using an already running daemon)
      -s, --use-sim-time    Enable ROS simulation time
      -c CONTROLLER_MANAGER, --controller-manager CONTROLLER_MANAGER
                            Name of the controller manager ROS node
      --include-hidden-nodes
                            Consider hidden nodes as well


Hi all. I have implemented position only IK in Ros1 using moveit. However, I
want to restrict the rotation of the end effector to some range. For example,
only 45 degrees of rotation is allowed around x and y axises, while no
rotation is allowed around z axis. Is it possible to implement position only
IK together with moveit_msgs/OrientationConstraint? Thank you very much for
your time. (I am using ROS kinetic)


####  3.1. L2026M


**Figure 1.** ( **A** ) Schematic representation of active ROS1 kinase domain
with crizotinib (PDB: ID 3ZBF). Mutation hotspots, indicated in red (L2026)
and blue (G2032), are depicted as spheres. ( **B** ) The zoomed-in region
shows the hydrophobic cluster involving residues L2000, F2004, F2103, A2106,
and F2075.


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**Figure 3.** Two-dimensional representations of inhibitor prototypes, ( **A**
) compound 1 (PDB: ID 7Z5X) and ( **B** ) compound 2 (PDB: ID 7Z5W), with the
following color scheme for the atoms: carbon (grey), oxygen (red), nitrogen
(blue), sulfur (yellow), and fluorine (cyan). Interactions were analyzed and
plotted using Discovery Studio Visualizer.


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  38. Gendarme, S.; Bylicki, O.; Chouaid, C.; Guisier, F. ROS-1 fusions in non-small-cell lung cancer: Evidence to date.  Curr. Oncol.  **2022** ,  29  , 641–658. [ [ Google Scholar ](https://scholar.google.com/scholar_lookup?title=ROS-1+fusions+in+non-small-cell+lung+cancer:+Evidence+to+date&author=Gendarme,+S.&author=Bylicki,+O.&author=Chouaid,+C.&author=Guisier,+F.&publication_year=2022&journal=Curr.+Oncol.&volume=29&pages=641%E2%80%93658&doi=10.3390/curroncol29020057) ] [ [ CrossRef ](https://doi.org/10.3390/curroncol29020057) ]


This research was funded by a bursary from the University of Groningen.


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    int main(int argc, char **argv){
      ros::init(argc, argv, "sensor");
      auto node = Sensor();
      ros::spin();
      return 0;
    }


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[ **updated 2022-07-02 02:05:46 -0500  ** ](/questions/403250/revisions/)


Despite compound mutations being commonly found in most of the kinases
targeted in clinical studies, up to the moment we finalized this review, no
reports of double ROS1 mutations could be found in patient-related material.
Resistance screening, exposing cells harboring ROS1 fusion, attempts to
predict future double mutations and their response to kinase inhibitors.
Treatment of Ba/F3 cells presenting CD74-ROS1  G2032R  with increasing doses
of cabozantinib or foretinib led to a rise in secondary mutations at positions
E1974, F2004, I2009, E2020, F2075, N2112, D2113, R2116, M2128, D2143, L2223,
and N2224K (  Figure 7  ) [  4  ]. However, the structural impact of these
double mutants on ROS1 dynamics and their limited sensitivity to kinase
inhibitors remain unknown.


Asked: ** 2022-07-01 10:21:39 -0500  **


Cell-based resistance screening performed with Ba/F3 in either native or
G2032R CD74-ROS1 also provided additional identification of single or double
mutants. Once performed on native CD74-ROS1 cell lines, such studies linked
the resistance to cabozantinib with mutations involving F2004 and F2075,
residues described as interaction spots for type II inhibitors [  4  ].
Previous reports had already indicated such residues as possible hotspots for
type II resistance due to analogous positions on ALK resistance to kinase
inhibitors [  36  ].


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In parallel, Petrovic also crystallized an ALK inhibitor derived from
crizotinib with the ROS1 kinase domain (PDB: ID 7Z5X). This analog conserved
the hinge-binding amino pyridine scaffold while modifying the two tails to
improve the pharmacokinetic and inhibitory profiles. The piperidine ring was
substituted with a 1,2-propanediol group, which interacted with the D2033
residue, and a network of hydrogen bonds was mediated by water molecules.
Despite conserving the fluorine atom in the 2-6-dichloro-3-fluoro phenyl ring,
one chlorine atom was removed while the other was substituted by a triazole
ring. In this crystal structure, the five-membered ring engages in an
intramolecular hydrogen bond with the hydroxyl attached to the thiazole ring
through a water molecule bridge (  Figure 3  ) [  12  ].


Groningen Biomolecular Sciences and Biotechnology Institute, University of
Groningen, 9700 AB Groningen, The Netherlands


      * [ Vilachã, J. F. ](http://www.pubmed.gov/?cmd=Search&term=Juliana%20F.%20Vilach%C3%A3)
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References


March 16, 2023  ·  3 min  read


###  Create a sensor node to simulate object detection


Tsjerk A. Wassenaar


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MD simulations also indicated that the presence of asparagine at position 2033
induced neighboring residue reorientation that would clash with the protonated
piperidine ring of crizotinib. Structural alignment of the structural ensemble
obtained from MD simulations with the crystal complex of ROS1–crizotinib
indicated an electrostatic repulsion between the positively charged nitrogen
in crizotinib and N2033. This is not observed for cabozantinib, as the nearest
atom of cabozantinib is 5 Å from position 2033 in both the native and mutant [
34  ].


These mutations are often associated with activation of the kinase domain
and/or resistance to kinase inhibitors [  8  ]. Understanding the mechanism
driving this event can aid the selection of drugs to be prioritized for
patient treatment or even lead to the development of novel drugs with a higher
affinity for the mutated kinase [  9  ,  10  ]. These mechanisms are driven by
structural changes linked to the nature of the mutation [  11  ]. The
characterization of the native kinase domain is critical to (I) understand the
structural features of this kinase in the bound or apo states and, (II)
compare, on a structural level, the overall folding in the presence of
mutations. In the case of ROS1, the use of X-ray crystallography was crucial
in understanding the binding profile of different kinase inhibitors. However,
there is a limitation in four structures available to this day at the Protein
Data Bank (PDB). All of them are from the wild-type ROS1 kinase domain;
additionally, all are bounded to a small molecule [  5  ,  6  ,  12  ].


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    class TfListener : ros::NodeHandle{
    private:
      // Subscription to pose published by sensor node
      ros::Subscriber pose_sub_;
      // Buffer that stores several seconds of transforms for easy lookup by the listener
      tf2_ros::Buffer tf_buffer_;
      // Listener for the broadcast transform message
      tf2_ros::TransformListener* tf_listener_;
      // Pose in source frame (`sensor_link`)
      geometry_msgs::PoseStamped pose_in_;
      // Pose in target frame (`arm_end_link`)
      geometry_msgs::PoseStamped pose_out_;


Dr. Tsjerk A Wassenaar is a pharmaceutical scientist and computational
chemist, rooted in medicinal chemistry and neuropharmacology and has a
doctorate in the Natural Sciences (Molecular Dynamics). He is strongly
interested in the biomolecular processes involved in protein-protein and
protein-ligand interactions. Currently, he is a Senior Lecturer in
Bioinformatics at the Data Science for Life Sciences at the Hanze University
of Applied Sciences Groningen.


##  1\. Introduction


![MDPI](https://pub.mdpi-res.com/img/design/mdpi-pub-logo-white-
small.png?71d18e5f805839ab?1713167732)


  *[
              2022-07-01 10:21:39 -0500
             ]: 2022-07-01 10:21:39 -0500
  *[
              2022-07-02 02:05:46 -0500
             ]: 2022-07-02 02:05:46 -0500
  *[
             2022-07-03 04:34:35 -0500
            ]: 2022-07-03 04:34:35 -0500
  *[
        2022-07-01 10:21:39 -0500
       ]: 2022-07-01 10:21:39 -0500
  *[
        2024-04-17 20:23:23 -0500
       ]: 2024-04-17 20:23:23 -0500


Prof. Dr. Siewert J. Marrink is a Professor and Head of Molecular Dynamics
Group, University of Groningen, The Netherlands. He graduated in 1989 and
obtained MSc from Faculty of Natural Sciences, University of Groningen, where
he completed his Ph.D. study in 1994. Then, he served as a Contract Researcher
at the BASF Ludwigshafen, Germany in 1995. Subsequently, as a Postdoctoral
Fellow, he went to Max Planck Institute for Biology Tübingen, Germany,
Department of Applied Mathematics, Australian National University, Australia,
Petroleum Cooperative Research Centre, University of New South Wales,
Australia, and Faculty of Natural Sciences, University of Groningen, The
Netherlands from 1996 to 2005. His research is aimed at an understanding of
(bio)molecular processes, using multiscale molecular dynamics simulations.
Besides, he is a Board Member of GBB, the Director of Berendsen Center,
Editorial Board Member of Biophysical Journal, Panel member of ERC
consolidator grant, etc.


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##  Conflicts of Interest


    $ ros2 control list_hardware_components
    Hardware Component 0
        name: RRBot
        type: system
        plugin name: ros2_control_demo_hardware/RRBotSystemPositionOnlyHardware
        state: id=3 label=active


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##  reload_controller_libraries  


Email address


Let’s first publish the transforms between our ` base_link ` and both `
arm_base_link ` and ` sensor_link ` . Use the ` static_transform_publisher `
we’ve learned in the [ previous post ](/blog/publishing-and-visualizing-
ros1-transforms) :


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$ rosrun transforms tf_broadcaster


This hypothesis was later supported by MD and free energy calculations.
Despite the MM-PBSA/GBSA calculations differing from experimentally determined
binding free energies, the magnitude difference observed between the WT and
G2032R was replicated. In the mutant, interaction with E2030, M2029, and L1951
residues was weaker, comparable with a similar analysis for crizotinib in the
WT binding pocket. In addition, it was shown that despite the mutated R2032
side chain’s favorable interaction with lorlatinib, its contribution was
comparable to G2032 in the WT protein. As was shown for crizotinib, the
reduced affinity of lorlatinib was associated with an increase in the
conformational entropy [  33  ].


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##  Article Metrics


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##  Comments


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Compile your package with ` $ catkin_make ` .


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The following commands support interacting with the ` controller_manager  `
from the command line. They are available through the standard ROS2 CLI
framework.


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      void poseCallback(const geometry_msgs::PoseStamped msg) {
        try {
          // Store the incoming pose in pose_in_
          pose_in_ = msg;
          // Transforms the pose between the source frame and target frame
          tf_buffer_.transform<geometry_msgs::PoseStamped>(pose_in_, pose_out_,
            "arm_end_link", ros::Duration(1));
          // Log coordinates of pose in target frame
          ROS_INFO("Object pose in 'arm_end_link' is:\n x,y,z = %.1f,%.1f,%.1f",
            pose_out_.pose.position.x,
            pose_out_.pose.position.y,
            pose_out_.pose.position.z);
        } catch (const tf2::TransformException & ex) {
          ROS_WARN("Could not find object position in 'arm_end_link' frame.");
          return;
        }
      }


###  Follow MDPI


**Figure 6.** Representation of point mutations in the ROS1 kinase domain: (
**A** ) L2026M, ( **B** ) G2032R, and ( **C** ) D2033N. In all figures, the
native ROS1 is represented in green with the mutated residues represented in
yellow, while being superimposed with the native counter partner residue. Key
structural motifs such as the G-loop and the  α  C-helix are highlighted in
the figures to aid identification of their location.


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Gatekeeper mutations are a common class of mutations in kinases. These
mutations often render kinase inhibitors ineffective due to an increase in
steric clashes in ATP. Reports of crizotinib’s interaction with ROS1  L2026M
were associated with the resistance to entropic changes that were minimized
for lorlatinib. However, a deeper understanding of how this mutation affects
the kinase domain of ROS1 and the efficacy of other kinase inhibitors is
needed. The valuable characterization of the native and mutated (D2113N)
inactive conformation of ROS1 provides insights into the binding of type II
inhibitors. The contribution of these models and further MD simulations has
become more significant due to the lack of an experimentally determined
structure of the ROS1 kinase domain in its inactive conformation.


Define a ` Sensor ` class with the following private variables:


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##  Stats


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21  ●  3  ●  5  ●  7


    # A set of constraints that the IK must obey; by default, this set of constraints is empty
    Constraints constraints


Despite the G2032R mutation’s association with crizotinib resistance, its
analog lorlatinib was efficient in the inhibition of the catalytic activity of
Ba/F3 cells exhibiting the fusion of CD74 and ROS1  G2032R  [  6  ]. As
previously mentioned, the use of homology modeling associated the resistance
of this mutation to crizotinib with a clash between the side chain of the
mutated R2032 and the pyrazole and piperidine rings of crizotinib. It was
proposed that this clash would be significantly reduced due to the absence of
the piperidine ring and the conformational restraint of the pyrazole ring
present on lorlatinib [  6  ].


####  3.3. D2033N


[ pickplace demo fails in moveit task constructor tutorial
](/question/370153/pickplace-demo-fails-in-moveit-task-constructor-tutorial/)


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With the ROS 1 [ ` tf2 ` library ](http://wiki.ros.org/tf2) , we can easily
transform our object’s position across frames – all without worrying about any
of the complicated mathematical operations happening under the hood – and
deduce how our arm needs to move to complete this task.


In this tutorial, we'll learn how ROS 1 transforms can help us calculate the
position of an object not explicitly linked to a robot – in relation to both
the sensor that detected it and the actuator that will interact with it.


Analysis of MD simulations of the inactive ROS1  WT  indicated a more rigid
P/G-loop. The same pattern is observed for the activation motif; in the
inactive ROS1 model, this motif is more rigid due to its proximity to the
P-loop and the  α  C-helix. The rigidity observed for the  α  C-helix is due
to the proximity of the Q2012 residue to the C-terminal segment of the same
helix, restricting its movement toward the catalytic site, which can explain
the average pocket volumes for ROS1 and ALK being 186 Å  3  and 235 Å  3  ,
respectively. Altogether, it was demonstrated that despite the significant
sequence homology between ROS1 and ALK, discrepancies in the rigidity and
motion of regulatory motifs contribute to the difference observed in the
specificity pocket of each kinase and these pockets’ volumes [  4  ].
Furthermore, the same inactive ROS1 model was used in relaxed complex scheme
(RCS) studies to propose a binding pose for cabozantinib, a type II kinase
inhibitor. The proposed binding mode shows the quinoline moiety interacting
with the hinge through hydrogen bonds with residue E2027 and M2029, as
crizotinib. The aryl linker engages in aromatic stacking with residue F2103
from the DFG motif, while the carboxamide moiety and the K1980 residue
interact through a hydrogen bond. The fluorophenyl tail is proposed to be
buried in the specificity pocket and interacts with F2004, a residue present
in the phenylalanine pocket located at the end of the  α  C-helix, and F2075
through aromatic stacking interactions. The additional residues M2001, L2070,
and I2100 contribute to hydrophobic interactions with this drug (  Figure 4  )
[  4  ].


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##  Share


Vilachã, Juliana F., Tsjerk A. Wassenaar, and Siewert J. Marrink. 2024\.
"Structural Aspects of the ROS1 Kinase Domain and Oncogenic Mutations"
_Crystals_ 14, no. 2: 106. https://doi.org/10.3390/cryst14020106


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You will also need the ` tf_broadcaster ` that publishes the ` arm_end_link `
frame:


    $ ros2 control reload_controller_libraries -h
    usage: ros2 control reload_controller_libraries [-h] [--spin-time SPIN_TIME] [--force-kill] [-c CONTROLLER_MANAGER] [--include-hidden-nodes]

    Reload controller libraries

    optional arguments:
      -h, --help            show this help message and exit
      --spin-time SPIN_TIME
                            Spin time in seconds to wait for discovery (only applies when not using an already running daemon)
      --force-kill          Force stop of loaded controllers
      -c CONTROLLER_MANAGER, --controller-manager CONTROLLER_MANAGER
                            Name of the controller manager ROS node
      --include-hidden-nodes
                            Consider hidden nodes as well


Approaches relying on docking are often used to identify novel scaffolds;
however, they present a low success rate [  22  ]. The low rate of success may
be associated with the onerous step of identifying hits within an extensive
library, which can be time-consuming and often depends on visual analysis.
Altogether, virtual screening frequently provides false positives that do not
go further in the development pipeline. Aiming to improve the application of
docking in drug discovery, AstraZeneca (AZ) proposed a combination of
structure- and ligand-based drug design (SBDD and LBDD, respectively).
Starting from a set of five molecules identified by different approaches, but
with considerable ROS1 potency and lack of potency over neurotrophic receptor
tyrosine kinase 1 (TrKA) (a kinase anti-target), AZ identified novel ROS1
inhibitor prototypes. Besides consolidating the efficacy of the use of the
FastROCS approach and its use in a cloud computing platform, this work also
provided two crystal structures of novel ROS1 and ligand complexes [  12  ,
23  ].


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