A randomized kinematics‐based approach to pharmacophore‐constrained conformational search and database screening

Computational tools have greatly expedited the pharmaceutical drug design process in recent years. One common task in this process is the search of a large library for small molecules that can achieve both a low‐energy conformation and a prescribed pharmacophore. The pharmacophore expresses constraints on the 3D structure of the molecule by specifying relative atom positions that should be maintained to increase the likelihood that the molecule will bind with the receptor site. This article presents a pharmacophore‐based database screening system that has been designed, implemented, and tested on a molecular database. The primary focus of this article is on a simple, randomized conformational search technique that attempts to simultaneously reduce energy and maintain pharmacophore constraints. This enables the identification of molecules in a database that are likely to dock with a given protein, which can serve as a powerful aid in the search for better drug candidates. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 731–747, 2000

[1]  Gareth Jones,et al.  Pharmacophoric pattern matching in files of three-dimensional chemical structures: Comparison of conformational-searching algorithms for flexible searching , 1994, J. Chem. Inf. Comput. Sci..

[2]  Barry Robson,et al.  Novel algorithms for searching conformational space , 1994, J. Comput. Aided Mol. Des..

[3]  John Canny,et al.  The complexity of robot motion planning , 1988 .

[4]  Andrew Smellie,et al.  Analysis of Conformational Coverage, 1. Validation and Estimation of Coverage , 1995, J. Chem. Inf. Comput. Sci..

[5]  W. C. Still,et al.  The multiple minimum problem in molecular modeling. Tree searching internal coordinate conformational space , 1988 .

[6]  Zhiyong Zhang,et al.  New realization of loop driven direct CI , 1992 .

[7]  C. Lemmen,et al.  FLEXS: a method for fast flexible ligand superposition. , 1998, Journal of medicinal chemistry.

[8]  P Willett,et al.  Searching for pharmacophoric patterns in databases of three‐dimensional chemical structures , 1995, Journal of molecular recognition : JMR.

[9]  Philip M. Dean,et al.  An exploration of a novel strategy for superposing several flexible molecules , 1993, J. Comput. Aided Mol. Des..

[10]  Martin Saunders,et al.  Conformations of cycloheptadecane. A comparison of methods for conformational searching , 1990 .

[11]  P. Schleyer.  Encyclopedia of computational chemistry , 1998 .

[12]  N. W. Murrall,et al.  Conformational freedom in 3-D databases. 1. Techniques , 1990, J. Chem. Inf. Comput. Sci..

[13]  G. Chang,et al.  An internal-coordinate Monte Carlo method for searching conformational space , 1989 .

[14]  Regine Bohacek,et al.  Three-Dimensional Models of ACE and NEP Inhibitors and Their Use in the Design of Potent Dual ACE/NEP Inhibitors , 1996 .

[15]  Andrew Smellie,et al.  Poling: Promoting conformational variation , 1995, J. Comput. Chem..

[16]  A. K. Ghose,et al.  Conformational searching methods for small molecules. I. Study of the sybyl search method , 1993, J. Comput. Chem..

[17]  Andrew Smellie,et al.  Analysis of Conformational Coverage, 2. Applications of Conformational Models , 1995, J. Chem. Inf. Comput. Sci..

[18]  Jaroslav Koča,et al.  SINGLE-COORDINATE-DRIVING METHOD COUPLED WITH SIMULATED ANNEALING. AN EFFICIENT TOOL TO SEARCH CONFORMATIONAL SPACE , 1997 .

[19]  R S Bohacek,et al.  Definition and display of steric, hydrophobic, and hydrogen-bonding properties of ligand binding sites in proteins using Lee and Richards accessible surface: validation of a high-resolution graphical tool for drug design. , 1992, Journal of medicinal chemistry.

[20]  Gareth Jones,et al.  A genetic algorithm for flexible molecular overlay and pharmacophore elucidation , 1995, J. Comput. Aided Mol. Des..

[21]  I. Kuntz,et al.  Conformational analysis of flexible ligands in macromolecular receptor sites , 1992 .

[22]  M. Fournié-Zaluski,et al.  Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme with long duration of action. , 1996, Journal of medicinal chemistry.

[23]  A. Ghose,et al.  Determination of Pharmacophoric Geometry for Collagenase Inhibitors Using a Novel Computational Method and Its Verification Using Molecular Dynamics, NMR, and X-ray Crystallography , 1995 .

[24]  David A. Cox,et al.  Ideals, Varieties, and Algorithms , 1997 .

[25]  G Klebe,et al.  On the prediction of binding properties of drug molecules by comparative molecular field analysis. , 1993, Journal of medicinal chemistry.

[26]  Eric Fontain,et al.  Application of genetic algorithms in the field of constitutional similarity , 1992, J. Chem. Inf. Comput. Sci..

[27]  Phillip J. McKerrow,et al.  Introduction to robotics , 1991 .

[28]  N. Sepetov,et al.  Library of libraries: approach to synthetic combinatorial library design and screening of "pharmacophore" motifs. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Osman F. Güner,et al.  Use of flexible queries for searching conformationally flexible molecules in databases of three-dimensional structures , 1992, J. Chem. Inf. Comput. Sci..

[30]  Tad Hurst,et al.  Flexible 3D searching: The directed tweak technique , 1994, J. Chem. Inf. Comput. Sci..

[31]  Thomas E. Moock,et al.  Conformational searching in ISIS/3D databases , 1994, J. Chem. Inf. Comput. Sci..

[32]  Yvonne C. Martin,et al.  New strategies that improve the efficiency of the 3D design of bioactive molecules , 1993 .