A novel method of aligning molecules by local surface shape similarity

A novel shape-based method has been developed for overlaying a series of molecule surfaces into a common reference frame. The surfaces are represented by a set of circular patches of approximately constant curvature. Two molecules are overlaid using a clique-detection algorithm to find a set of patches in the two surfaces that correspond, and overlaying the molecules so that the similar patches on the two surfaces are coincident. The method is thus able to detect areas of local, rather than global, similarity. A consensus overlay for a group of molecules is performed by examining the scores of all pairwise overlays and performing a set of overlays with the highest scores. The utility of the method has been examined by comparing the overlaid and experimental configurations of 4 sets of molecules for which there are X-ray crystal structures of the molecules bound to a protein active site. Results for the overlays are generally encouraging. Of particular note is the correct prediction of the `reverse orientation' for ligands binding to human rhinovirus coat protein HRV14.

[1]  S. Kearsley.  An algorithm for the simultaneous superposition of a structural series , 1990 .

[2]  J. A. Grant,et al.  A fast method of molecular shape comparison: A simple application of a Gaussian description of molecular shape , 1996, J. Comput. Chem..

[3]  B. Lee,et al.  The interpretation of protein structures: estimation of static accessibility. , 1971, Journal of molecular biology.

[4]  R. Nussinov,et al.  Molecular shape comparisons in searches for active sites and functional similarity. , 1998, Protein engineering.

[5]  Jordi Mestres,et al.  MIMIC: A molecular‐field matching program. Exploiting applicability of molecular similarity approaches , 1997 .

[6]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[7]  Gerhard Klebe,et al.  What Can We Learn from Molecular Recognition in Protein–Ligand Complexes for the Design of New Drugs? , 1996 .

[8]  Peter Willett,et al.  Algorithms for the identification of three-dimensional maximal common substructures , 1987, J. Chem. Inf. Comput. Sci..

[9]  R. Huber,et al.  X‐ray crystal structure of the complex of human leukocyte elastase (PMN elastase) and the third domain of the turkey ovomucoid inhibitor. , 1986, The EMBO journal.

[10]  C. Bron,et al.  Algorithm 457: finding all cliques of an undirected graph , 1973 .

[11]  B. Masek,et al.  Molecular skins: A new concept for quantitative shape matching of a protein with its small molecule mimics , 1993, Proteins.

[12]  G. Maggiora,et al.  A molecular field-based similarity approach to pharmacophoric pattern recognition. , 1997, Journal of molecular graphics & modelling.

[13]  H. Wolfson,et al.  Examination of shape complementarity in docking of Unbound proteins , 1999, Proteins.

[14]  James A. McHugh,et al.  Algorithmic Graph Theory , 1986 .

[15]  B. Masek,et al.  Molecular shape comparison of angiotensin II receptor antagonists. , 1993, Journal of medicinal chemistry.

[16]  Gerhard Klebe,et al.  Superposition of molecules: Electron density fitting by application of fourier transforms , 1997 .

[17]  Peter Willett,et al.  Comparison of protein surfaces using a genetic algorithm , 1997, J. Comput. Aided Mol. Des..

[18]  Thomas Lengauer,et al.  RigFit: A new approach to superimposing ligand molecules , 1998, German Conference on Bioinformatics.

[19]  Andrew C. Good,et al.  Utilization of Gaussian functions for the rapid evaluation of molecular similarity , 1992, J. Chem. Inf. Comput. Sci..

[20]  Robert B. Hermann,et al.  OVID and SUPER: Two overlap programs for drug design , 1991, J. Comput. Aided Mol. Des..

[21]  R. Radhakrishnan,et al.  Crystal structure of the covalent complex formed by peptidyl α,α-difluoro-β-keto amide with porcine pancreatic elastase at 1.78-Å resolution , 1989 .

[22]  Ramon Carbo,et al.  How similar is a molecule to another? An electron density measure of similarity between two molecular structures , 1980 .

[23]  P. Weiner,et al.  Computer Simulation of Biomolecular Systems , 1997 .

[24]  H. Kubinyi,et al.  3D QSAR in drug design. , 2002 .

[25]  Gustavo A. Arteca,et al.  A complete shape characterization for molecular charge densities represented by Gaussian‐type functions , 1991 .