The present invention provides a novel method of superposing molecular conformations of compounds for drugs, agricultural chemicals, etc., and it can be applied in the process of determining bioactive conformation from many stable conformations.
The invention provides a novel technique of superposing molecular conformations of compounds that is utilizable for the creation of lead compounds for drugs, agricultural chemicals, etc., based on the exploration of the bioactive conformation and pharmacophore.
In computer assissted drug designs of drugs and agricultural chemicals, it is very important to determine the conformation of ligand molecule in the state of binding to proteins such as receptor and enzyme, that is, the bioactive conformation thereof. As a method of experimentally determining the bioactive conformation of this ligand molecule, X-ray crystallography of complex with proteins or NMR spectroscopy has been known. However, it is generally accompanied with many difficulties that the crystallization of proteins such as receptor and enzyme is difficult, that enough quantity for analysis cannot be obtained, that molecular weight is too large to analyze, and the like. For this reason, in computer assisted drug designs, an approach is taken to presume the bioactive conformation, based on the crystal structure of ligand molecule alone or the structure obtained from calculation by molecular mechanics or molecular orbital method in a system that does not clearly deal with the solvent molecules.
It has been considered that, even if the bioactive conformation may not be the same as the most stable conformation obtained from calculation, it comes to be a stable conformation not so away from the most stable conformation, in view of energy. Moreover, for the conformations of ligand molecules binding to the same receptor or enzyme, a common feature that there is the same characteristic group in the same site in three-dimensional space is considered, hence the superposition among characteristic groups of the stable conformations is effective for the extraction of bioactive conformation. For example, it appears to be also possible to sample many stable conformations using molecular dynamics calculation on some ligand molecules and perform the superposition among those stable conformations based on the constituting characteristic group to determine the bioactive conformation common to each ligand molecule.
For the superposition among molecules, it is common to perform so that the positions coincide with each other between the corresponding atoms. For this reason, an operation for determining beforehand the pharmacologically effective atoms of compounds is needed. However, the atomic positions are not needed to coincide for binding to proteins such as receptor and enzyme and, additionally, there are many receptors for which even the existence, to say nothing of information of three-dimensional structures thereof, is not grasped, so the problems are complicated. Hence, the results of interactive superposition tend to be influenced by the intuition and experience of analyst.
While, Y. C. Martin et al developed an automatic exploratory technique of superposition (DISCO) by improving the conventional technique of matching the distance between pharmacophore centers, wherein the allowable error was taken in for the coincidence of atomic positions and further the direction of hydrogen bond and the orientation of aromatic ring were also taken into account, and applied it to dopamine agonist and benzodiazepine agonist (Y. C. Martin et al, J. Compt.-Aided Mol. Design, 7, 83-102(1993)).
In others, techniques of evaluating the superposition from the similarity of the electron density, electrostatic potential and volume of molecule are reported by Carbo (R. Carbo, L. Leyda and M. Arnau, Int. J. Qant. Chem., 17, 1185-1189(1980); R. Carbo and L. Domingo, Int. J. Qant. Chem., 32, 517-545(1987)) and by Hodgkin (W. G. Richards and E. E. Hodgkin, Chemistry in Britain, 1141-1144(1988); E. E. Hodgkin and W. G. Richards, Int. J. Qant. Chem., 14, 105-110(1987)), and the automatic exploration of superposition can be realized with ASP package (C. Burt, W. G. Richards and P. Huxley, J. Comput. Chem., 11, 1139-1146(1990)).
In recent years, proceeding this further, T. D. Perkins et al developed a technique that took the similarity of volume, hydrogen bond and electrostatic potential into account and applied it to some inhibitors. Thereamong, the automatic exploration of superposition between serine protease inhibitors with different sizes attracts an attention (T. D. Perkins, J. E. J. Mills and P. M. Dean, J. Compt.-Aided Mol. Design, 9, 479-490(1995)).
However, the method of Y. C. Martin et al has restrictions that the number of functional groups constituting the pharmacophore should be equal between compounds, that the correspondence between atoms and between functional groups should be taken into account, and the like.
Also, the method of T. D. Perkins et al takes considerable calculating time on the whole, and it requires difficulty to determine the bioactive conformation using this technique.
For this reason, simpler and more rapid method of superposing the molecules of compounds has been required.
The inventors studied diligently to solve the subject aforementioned and, in the method of superposing the molecular conformations of compounds, they have found a method of performing the superposition based on the properties of characteristic group constituting that molecule of compounds, leading to the completion of the invention.