Answers.Body: <p><strong>A positive logP is good (hydrophobic)</strong>, but high results in ADMET problems (cytochromes break overly hydrophobic compounds) and aggregation (gunk, tar, crud are words happily thrown around). However, in most cases the logP is not greater than +3 because good binding is result of hydrogen bonds etc —some bad algorithms will suggest a polyaromatic hydrocarbon that makes lots of pi-pi interactions but these are few.</p>
  <p>Confusingly, <strong>a high synthetic accessibility score is bad (hard)</strong>. 3 is the average and 10 is basically something impossible. This score is how hard it is to make (i.e. pricier), which is one of the major drivers.</p>
  <p>The number of cycles is number of rings. Even if you get pi-pi, cation-pi and sulfur-pi bonds you also get aggregation due to stacking (a crud). So is somewhat bad.</p>
  <p>So basically that score is</p>
  <pre><code>high=good minus high=bad minus high=bad
  </code></pre>
  <p>If difference in relative Gibbs energy of binding is thrown it, negative ∆∆G is good, so that would be subtracted. As its atom count dependent ligand efficiency is better, but that ranges from 0 to -1.2 kcal/mol. So would need scaling.</p>
  
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Answers.Body: <p>You were trapped by arXiv versioning convention that shows you the <strong>latest</strong> version of the preprint as default. It seems that this experiment was removed from the final publication.</p>
  <p>If you have a look at the v1 (<a href="https://arxiv.org/abs/1610.02415v1" rel="nofollow noreferrer">https://arxiv.org/abs/1610.02415v1</a>) instead of the latest version (v3), you find the explanation:</p>
  <blockquote>
  <p>As a simple example, we first attempt to maximize the water-octanol
  partition coefficient <span class="math-container">$logP$</span>, as estimated by RDkit. [43] <span class="math-container">$logP$</span> is an
  important element in characterizing the druglikeness of a molecule,
  and is of interest in drug design.  To ensure that the resulting
  molecules to be easy to synthesize in practice, we also incorporate
  the synthetic accessibility [44] (SA) score into our objective. Our
  initial experiments, optimizing only the <span class="math-container">$logP$</span> and SA scores, produced
  novel molecules, but ones having unrealistically large rings of carbon
  atoms. To avoid this problem, we added a penalty for having carbon
  rings of size larger than 6 to our objective. Thus our preferred
  objective is, for a given molecule m, given by:
  <span class="math-container">$J(m) = logP(m) − SA(m) − ring-penalty(m)$</span>,          (1)</p>
  <p>where the scores <span class="math-container">$logP(m)$</span>, <span class="math-container">$SA(m)$</span>, and <span class="math-container">$ring-penalty(m)$</span> are normalized to
  have zero mean.</p>
  </blockquote>
  
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Body: <p>I found that <a href="https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five" rel="nofollow noreferrer">Lipinski's rule of five</a> states that Log P (octanol-water partition coefficient, lipophilicity measure) usually should not exceed 5.</p>
  <p>Many papers about drug discovery machine learning models tell about maximization of &quot;penalized logP&quot;, but the paper they refer in the end does not contain any information on it. Let me show that.</p>
  <p>Let's check <a href="https://arxiv.org/pdf/1802.04364.pdf" rel="nofollow noreferrer">1</a>, here we read about penalized log P:</p>
  <blockquote>
  <p>The second task is to produce novel molecules with desired properties. Following (Kusner et al., 2017), our target chemical
  property y(·)is octanol-water partition coefficients (logP) penalized
  by the synthetic accessibility (SA)score and number of long cycles</p>
  <pre><code>y(m) = logP(m)−SA(m)−cycle(m) 
  </code></pre>
  <p>where cycle(m)counts the number of rings that have more than six atoms.</p>
  </blockquote>
  <p>Then we go into <a href="https://arxiv.org/pdf/1703.01925.pdf" rel="nofollow noreferrer">Kusner et al., 2017</a>:</p>
  <blockquote>
  <p>For the second optimization problem, we follow (Gómez-Bombarelli et al., 2016b) and optimize the drug properties of molecules. Our goal
  is to maximize the water-octanol partition coefficient (logP), an
  important metric in drug design that characterizes the drug-likeness
  of a molecule.As in Gómez-Bombarelli et al. (2016b) we consider a
  penalized logP score that takes into account other molecular
  properties such as ring size and synthetic accessibility (Ertl &amp;
  Schuffenhauer, 2009).</p>
  </blockquote>
  <p>Here is <a href="https://arxiv.org/pdf/1610.02415.pdf" rel="nofollow noreferrer">Gómez-Bombarelli, 2016</a> and it seems to contain nothing on the topic (I can be mistaken, please point me then), except</p>
  <blockquote>
  <p>The objective we chose to optimize was 5×QED−SAS, where QED is the Quantitative Estimation of Drug-likeness (QED),37 and SAS is the
  Synthetic Accessibility score.36Thisobjective represents a rough
  estimate of finding the most drug-like molecule that is also easy to
  synthesize.</p>
  </blockquote>
  <p>Other examples of the papers also leading to the same papers are <a href="https://arxiv.org/pdf/1806.02473.pdf" rel="nofollow noreferrer">2</a>, <a href="https://www.nature.com/articles/s41598-019-47148-x" rel="nofollow noreferrer">3</a>, etc.</p>
  <p>What does penalized logP mean for drug-likeliness and why it should be maximized?</p>
  
Tags: <drugs><small-molecules>
Title: Why do molecular generation models maximize “penalized logP” as a measure of drug-likeliness?
ThreadText: # Why do molecular generation models maximize “penalized logP” as a measure of drug-likeliness?
  
  (Asked by: username_0 on 2021-03-29)
  
  I found that [Lipinski's rule of five](https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five) states that Log P (octanol-water partition coefficient, lipophilicity measure) usually should not exceed 5.
  
  Many papers about drug discovery machine learning models tell about maximization of "penalized logP", but the paper they refer in the end does not contain any information on it. Let me show that.
  
  Let's check [1](https://arxiv.org/pdf/1802.04364.pdf), here we read about penalized log P:
  
  > The second task is to produce novel molecules with desired properties. Following (Kusner et al., 2017), our target chemical
  > property y(·)is octanol-water partition coefficients (logP) penalized
  > by the synthetic accessibility (SA)score and number of long cycles
  >
  > ```
  > y(m) = logP(m)−SA(m)−cycle(m) 
  >
  > ```
  >
  > where cycle(m)counts the number of rings that have more than six atoms.
  
  Then we go into [Kusner et al., 2017](https://arxiv.org/pdf/1703.01925.pdf):
  
  > For the second optimization problem, we follow (Gómez-Bombarelli et al., 2016b) and optimize the drug properties of molecules. Our goal
  > is to maximize the water-octanol partition coefficient (logP), an
  > important metric in drug design that characterizes the drug-likeness
  > of a molecule.As in Gómez-Bombarelli et al. (2016b) we consider a
  > penalized logP score that takes into account other molecular
  > properties such as ring size and synthetic accessibility (Ertl &
  > Schuffenhauer, 2009).
  
  Here is [Gómez-Bombarelli, 2016](https://arxiv.org/pdf/1610.02415.pdf) and it seems to contain nothing on the topic (I can be mistaken, please point me then), except
  
  > The objective we chose to optimize was 5×QED−SAS, where QED is the Quantitative Estimation of Drug-likeness (QED),37 and SAS is the
  > Synthetic Accessibility score.36Thisobjective represents a rough
  > estimate of finding the most drug-like molecule that is also easy to
  > synthesize.
  
  Other examples of the papers also leading to the same papers are [2](https://arxiv.org/pdf/1806.02473.pdf), [3](https://www.nature.com/articles/s41598-019-47148-x), etc.
  
  What does penalized logP mean for drug-likeliness and why it should be maximized?
  
  **Tags:** drugs, small-molecules
  
  
  ---
  
  ## 2 answers
  
  ### Answer by username_1 on 2021-03-30. Score: 2 | Accepted answer
  
  **A positive logP is good (hydrophobic)**, but high results in ADMET problems (cytochromes break overly hydrophobic compounds) and aggregation (gunk, tar, crud are words happily thrown around). However, in most cases the logP is not greater than +3 because good binding is result of hydrogen bonds etc —some bad algorithms will suggest a polyaromatic hydrocarbon that makes lots of pi-pi interactions but these are few.
  
  Confusingly, **a high synthetic accessibility score is bad (hard)**. 3 is the average and 10 is basically something impossible. This score is how hard it is to make (i.e. pricier), which is one of the major drivers.
  
  The number of cycles is number of rings. Even if you get pi-pi, cation-pi and sulfur-pi bonds you also get aggregation due to stacking (a crud). So is somewhat bad.
  
  So basically that score is
  
  ```
  high=good minus high=bad minus high=bad
  
  ```
  
  If difference in relative Gibbs energy of binding is thrown it, negative ∆∆G is good, so that would be subtracted. As its atom count dependent ligand efficiency is better, but that ranges from 0 to -1.2 kcal/mol. So would need scaling.
  
  
  ---
  
  ### Answer by username_2 on 2022-07-01. Score: 1
  
  You were trapped by arXiv versioning convention that shows you the **latest** version of the preprint as default. It seems that this experiment was removed from the final publication.
  
  If you have a look at the v1 (<https://arxiv.org/abs/1610.02415v1>) instead of the latest version (v3), you find the explanation:
  
  > As a simple example, we first attempt to maximize the water-octanol
  > partition coefficient $logP$, as estimated by RDkit. [43] $logP$ is an
  > important element in characterizing the druglikeness of a molecule,
  > and is of interest in drug design. To ensure that the resulting
  > molecules to be easy to synthesize in practice, we also incorporate
  > the synthetic accessibility [44] (SA) score into our objective. Our
  > initial experiments, optimizing only the $logP$ and SA scores, produced
  > novel molecules, but ones having unrealistically large rings of carbon
  > atoms. To avoid this problem, we added a penalty for having carbon
  > rings of size larger than 6 to our objective. Thus our preferred
  > objective is, for a given molecule m, given by:
  > $J(m) = logP(m) − SA(m) − ring-penalty(m)$, (1)
  >
  > where the scores $logP(m)$, $SA(m)$, and $ring-penalty(m)$ are normalized to
  > have zero mean.
  
  
  ---
  
  