Development and validation of a genetic algorithm for flexible docking.

Prediction of small molecule binding modes to macromolecules of known three-dimensional structure is a problem of paramount importance in rational drug design (the "docking" problem). We report the development and validation of the program GOLD (Genetic Optimisation for Ligand Docking). GOLD is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Numerous enhancements and modifications have been applied to the original technique resulting in a substantial increase in the reliability and the applicability of the algorithm. The advanced algorithm has been tested on a dataset of 100 complexes extracted from the Brookhaven Protein DataBank. When used to dock the ligand back into the binding site, GOLD achieved a 71% success rate in identifying the experimental binding mode.

[1]  A T Brünger,et al.  2.9 A resolution structure of an anti-dinitrophenyl-spin-label monoclonal antibody Fab fragment with bound hapten. , 1991, Journal of molecular biology.

[2]  M Ikehara,et al.  Crystal structure of ribonuclease Ms (as a ribonuclease T1 homologue) complexed with a guanylyl-3',5'-cytidine analogue. , 1993, Biochemistry.

[3]  J. Sussman,et al.  Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[4]  K S Wilson,et al.  Crystal structure of inorganic pyrophosphatase from Thermus thermophilus , 1994, Protein Science.

[5]  Reiko Tanese,et al.  Distributed Genetic Algorithms , 1989, ICGA.

[6]  Robert P. Sheridan,et al.  FLOG: A system to select ‘quasi-flexible’ ligands complementary to a receptor of known three-dimensional structure , 1994, J. Comput. Aided Mol. Des..

[7]  M G Rossmann,et al.  Structural analysis of antiviral agents that interact with the capsid of human rhinoviruses , 1990, Proteins.

[8]  O. Herzberg,et al.  Refined crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.0 A resolution. , 1991, Journal of molecular biology.

[9]  M. L. Mason,et al.  Three‐dimensional structure of a fluorescein–Fab complex crystallized in 2‐methyl‐2,4‐pentanediol , 1989, Proteins.

[10]  J C Sacchettini,et al.  Escherichia coli-derived rat intestinal fatty acid binding protein with bound myristate at 1.5 A resolution and I-FABPArg106-->Gln with bound oleate at 1.74 A resolution. , 1994, The Journal of biological chemistry.

[11]  A. North,et al.  Pheromone binding to two rodent urinary proteins revealed by X-ray crystallography , 1992, Nature.

[12]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1978, Archives of biochemistry and biophysics.

[13]  J. Scott Dixon,et al.  A good ligand is hard to find: Automated docking methods , 1993 .

[14]  G. D. Smith,et al.  The structure of a rhombohedral R6 insulin hexamer that binds phenol , 1992, Biopolymers.

[15]  Gerhard Klebe,et al.  Mapping common molecular fragments in crystal structures to explore conformation and configuration space under the conditions of a molecular environment , 1994 .

[16]  A M Hassell,et al.  Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays. , 1992, Biochemistry.

[17]  R F Standaert,et al.  Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin. , 1993, Journal of molecular biology.

[18]  L. Banaszak,et al.  X-ray crystallographic structures of adipocyte lipid-binding protein complexed with palmitate and hexadecanesulfonic acid. Properties of cavity binding sites. , 1994, Biochemistry.

[19]  T. Nonaka,et al.  Crystal structure of ribonuclease Ms (as a ribonuclease T1 homologue) complexed with a guanylyl-3',5'-cytidine analogue. , 1993 .

[20]  R. Palmer,et al.  STRUCTURE OF THE CRYSTALLINE COMPLEX OF CYTIDYLIC ACID (2'-CMP) WITH RIBONUCLEASE AT 1.6 ANGSTROMS RESOLUTION , 1994 .

[21]  J. Kraut,et al.  Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. , 1994, Biochemistry.

[22]  H Brandstetter,et al.  Refined 2.3 A X-ray crystal structure of bovine thrombin complexes formed with the benzamidine and arginine-based thrombin inhibitors NAPAP, 4-TAPAP and MQPA. A starting point for improving antithrombotics. , 1992, Journal of molecular biology.

[23]  Rober t C. Glen.  A fast empirical method for the calculation of molecular polarizability , 1994, J. Comput. Aided Mol. Des..

[24]  Ernö Pretsch,et al.  Application of genetic algorithms in molecular modeling , 1994, J. Comput. Chem..

[25]  J M Blaney,et al.  A geometric approach to macromolecule-ligand interactions. , 1982, Journal of molecular biology.

[26]  C. Frömmel,et al.  The automatic search for ligand binding sites in proteins of known three-dimensional structure using only geometric criteria. , 1996, Journal of molecular biology.

[27]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[28]  William L. Duax,et al.  Mechanism of inhibition of 3α,20β-hydroxysteroid dehydrogenaseby a licorice-derived steroidal inhibitor , 1994 .

[29]  M C Nicklaus,et al.  Conformational changes of small molecules binding to proteins. , 1995, Bioorganic & medicinal chemistry.

[30]  Jon Clardy,et al.  DESIGN, SYNTHESIS, AND KINETIC EVALUATION OF HIGH-AFFINITY FKBP LIGANDS AND THE X-RAY CRYSTAL-STRUCTURES OF THEIR COMPLEXES WITH FKBP12. , 1994 .

[31]  W. V. van Gunsteren,et al.  An efficient mean solvation force model for use in molecular dynamics simulations of proteins in aqueous solution. , 1996, Journal of molecular biology.

[32]  Gennady M Verkhivker,et al.  Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. , 1995, Chemistry & biology.

[33]  J M Burridge,et al.  Refined crystal structures of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim. , 1985, The Journal of biological chemistry.

[34]  Eiji Osawa,et al.  Corner flapping: a simple and fast algorithm for exhaustive generation of ring conformations , 1989 .

[35]  H. H. Jaffé,et al.  Electronegativity. I. Orbital Electronegativity of Neutral Atoms , 1962 .

[36]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[37]  R C Glen,et al.  Molecular recognition using a binary genetic search algorithm. , 1993, Journal of molecular graphics.

[38]  A Wlodawer,et al.  Nuclear magnetic resonance and neutron diffraction studies of the complex of ribonuclease A with uridine vanadate, a transition-state analogue. , 1985, Biochemistry.

[39]  Frank H. Allen,et al.  Correlation of the hydrogen‐bond acceptor properties of nitrogen with the geometry of the Nsp2→Nsp3 transition in R1(X=)C–NR2R3 substructures: reaction pathway for the protonation of nitrogen , 1995 .

[40]  Christopher Bystroff,et al.  Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. , 1994, Biochemistry.

[41]  Lode Wyns,et al.  Structure of the crystalline complex of cytidylic acid (2'-CMP) with ribonuclease at 1.6 A resolution. Conservation of solvent sites in RNase-A high-resolution structures. , 1993, Acta crystallographica. Section D, Biological crystallography.

[42]  W G Laver,et al.  Structures of aromatic inhibitors of influenza virus neuraminidase. , 1995, Biochemistry.

[43]  Richard S. Judson,et al.  Docking flexible molecules: A case study of three proteins , 1995, J. Comput. Chem..

[44]  G L Kenyon,et al.  The role of lysine 166 in the mechanism of mandelate racemase from Pseudomonas putida: mechanistic and crystallographic evidence for stereospecific alkylation by (R)-alpha-phenylglycidate. , 1994, Biochemistry.

[45]  M. L. Connolly.  Analytical molecular surface calculation , 1983 .

[46]  M. Lewis.  Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays. , 1992 .

[47]  J. Delaney.  Finding and filling protein cavities using cellular logic operations. , 1992, Journal of Molecular Graphics.

[48]  John H. Holland,et al.  Adaptation in Natural and Artificial Systems: An Introductory Analysis with Applications to Biology, Control, and Artificial Intelligence , 1992 .

[49]  L. Darrell Whitley,et al.  Optimization Using Distributed Genetic Algorithms , 1990, PPSN.

[50]  G. Cohen,et al.  On the specificity of antibody/antigen interactions: phosphocholine binding to McPC603 and the correlation of three-dimensional structure and sequence data. , 1985, Annales de l'Institut Pasteur. Immunologie.

[51]  Mark C. Surles,et al.  Sculpting proteins interactively: Continual energy minimization embedded in a graphical modeling system , 1994, Protein science : a publication of the Protein Society.

[52]  D. Filman,et al.  Structural factors that control conformational transitions and serotype specificity in type 3 poliovirus. , 1989, The EMBO journal.

[53]  K. Murthy,et al.  The crystal structures at 2.2-A resolution of hydroxyethylene-based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations. , 1994 .

[54]  K H Murthy,et al.  The crystal structures at 2.2-A resolution of hydroxyethylene-based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations. , 1992, The Journal of biological chemistry.

[55]  Kalyanmoy Deb,et al.  An Investigation of Niche and Species Formation in Genetic Function Optimization , 1989, ICGA.

[56]  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..

[57]  R. Cramer,et al.  Validation of the general purpose tripos 5.2 force field , 1989 .

[58]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[59]  R J Fletterick,et al.  Crystal structure of a catalytic antibody with a serine protease active site. , 1994, Science.

[60]  John H. Holland,et al.  Adaptation in Natural and Artificial Systems: An Introductory Analysis with Applications to Biology, Control, and Artificial Intelligence , 1992 .

[61]  T. Steitz,et al.  Structural basis of asymmetry in the human immunodeficiency virus type 1 reverse transcriptase heterodimer. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[62]  R. Williams,et al.  Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14. , 1993, Journal of molecular biology.

[63]  Anthony J. Stone,et al.  An intermolecular perturbation theory for the region of moderate overlap , 1984 .

[64]  D. Goodsell,et al.  Automated docking of substrates to proteins by simulated annealing , 1990, Proteins.

[65]  P Willett,et al.  Docking small-molecule ligands into active sites. , 1995, Current opinion in biotechnology.

[66]  J. Scott Dixon,et al.  Flexible ligand docking using a genetic algorithm , 1995, J. Comput. Aided Mol. Des..

[67]  S. Sun,et al.  Reduced representation model of protein structure prediction: Statistical potential and genetic algorithms , 1993, Protein science : a publication of the Protein Society.

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

[69]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[70]  A. Treasurywala,et al.  A genetic algorithm based method for docking flexible molecules , 1994 .

[71]  A. Leslie.  Refined crystal structure of type III chloramphenicol acetyltransferase at 1.75 A resolution. , 1990, Journal of molecular biology.

[72]  David E. Goldberg,et al.  Genetic Algorithms in Search Optimization and Machine Learning , 1988 .

[73]  O. Herzberg,et al.  Structure of a phosphonate-inhibited beta-lactamase. An analog of the tetrahedral transition state/intermediate of beta-lactam hydrolysis. , 1993, Journal of molecular biology.

[74]  C. Stout,et al.  Crystal structures of aconitase with trans-aconitate and nitrocitrate bound. , 1993, Journal of molecular biology.

[75]  Ajay,et al.  Computational methods to predict binding free energy in ligand-receptor complexes. , 1995, Journal of medicinal chemistry.

[76]  L. Tong,et al.  Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere. , 1995, Structure.

[77]  A. Edmundson,et al.  Principles and pitfalls in designing site‐directed peptide ligands , 1993, Proteins.

[78]  J. Bolin,et al.  Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. , 1982, The Journal of biological chemistry.

[79]  G A Petsko,et al.  Structure and activity of two photoreversible cinnamates bound to chymotrypsin. , 1990, Biochemistry.

[80]  J. Hamilton,et al.  The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution. , 1993, The Journal of biological chemistry.

[81]  Owen Johnson,et al.  The development of versions 3 and 4 of the Cambridge Structural Database System , 1991, J. Chem. Inf. Comput. Sci..

[82]  J. Glusker.  Structural aspects of metal liganding to functional groups in proteins. , 1991, Advances in protein chemistry.

[83]  J. Hamilton,et al.  The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30→Met variant to 1.7-Å resolution , 1993 .

[84]  Chris M. W. Ho,et al.  Cavity search: An algorithm for the isolation and display of cavity-like binding regions , 1990, J. Comput. Aided Mol. Des..

[85]  K. Diederichs,et al.  The refined structure of the complex between adenylate kinase from beef heart mitochondrial matrix and its substrate AMP at 1.85 A resolution. , 1991, Journal of molecular biology.

[86]  John Moult,et al.  Crystallographic Analysis of a Pepstatin Analogue Binding to the Aspartyl Proteinase Penicillopepsin at 1.8 Angstroms Resolution , 1994 .

[87]  T. Blundell,et al.  X-ray crystallographic analysis of inhibition of endothiapepsin by cyclohexyl renin inhibitors. , 1992, Biochemistry.

[88]  C. F. Curtiss,et al.  Molecular Theory Of Gases And Liquids , 1954 .

[89]  R M Stroud,et al.  Structures of thymidylate synthase with a C-terminal deletion: role of the C-terminus in alignment of 2'-deoxyuridine 5'-monophosphate and 5,10-methylenetetrahydrofolate. , 1993, Biochemistry.

[90]  R. Glen,et al.  Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. , 1995, Journal of molecular biology.

[91]  P Argos,et al.  Identifying the tertiary fold of small proteins with different topologies from sequence and secondary structure using the genetic algorithm and extended criteria specific for strand regions. , 1996, Journal of molecular biology.

[92]  Frank H. Allen,et al.  The Nature and Geometry of Intermolecular Interactions between Halogens and Oxygen or Nitrogen , 1996 .

[93]  R L Campbell,et al.  26-10 Fab-digoxin complex: affinity and specificity due to surface complementarity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[94]  John B. O. Mitchell,et al.  On the relative strengths of amide…amide and amide…water hydrogen bonds , 1991 .