Statistical relationships among docking scores for different protein binding sites

This report describes the existence of statistical relationships among scores computed with the DOCK program for a library of small molecules and a panel of protein binding sites. Multivariate relationships are observed in docking scores computed for a constant set of ligands in different binding sites of proteins that are dissimilar in structure and function. The structural basis for the correlations found among scores is analyzed in terms of size, shape and charge characteristics of the binding sites considered. Interestingly, these results parallel a growing body of evidence demonstrating the promiscuous behavior of small molecules in their interactions with macromolecules that could have an impact in future efforts in drug design.

[1]  P. Schultz,et al.  Immunological origins of binding and catalysis in a Diels-Alderase antibody. , 1998, Science.

[2]  I. Kuntz,et al.  Automated docking with grid‐based energy evaluation , 1992 .

[3]  A. Goldman,et al.  Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein , 1991, Science.

[4]  M. L. Connolly.  Solvent-accessible surfaces of proteins and nucleic acids. , 1983, Science.

[5]  I. Kuntz,et al.  Molecular similarity based on DOCK-generated fingerprints. , 1996, Journal of medicinal chemistry.

[6]  Alan J. Miller,et al.  Subset Selection in Regression , 1991 .

[7]  I. Kuntz.  Structure-Based Strategies for Drug Design and Discovery , 1992, Science.

[8]  I. Kuntz,et al.  Structure-based discovery of inhibitors of thymidylate synthase. , 1993, Science.

[9]  I. Kuntz,et al.  Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure. , 1988, Journal of medicinal chemistry.

[10]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

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

[12]  R. Stroud,et al.  Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folate. , 1990 .

[13]  I. G. Kamphuis,et al.  Structure of papain refined at 1.65 A resolution. , 1984, Journal of molecular biology.

[14]  Daniel A. Gschwend,et al.  Orientational sampling and rigid‐body minimization in molecular docking , 1993, Proteins.

[15]  Thomas Lengauer,et al.  Computational methods for biomolecular docking. , 1996, Current opinion in structural biology.

[16]  Alan J. Miller.  Subset Selection in Regression , 1992 .

[17]  I. Kuntz,et al.  Structure-Based Molecular Design , 1994 .

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

[19]  Elaine C. Meng,et al.  Evaluating docked complexes with the HINT exponential function and empirical atomic hydrophobicities , 1994, J. Comput. Aided Mol. Des..

[20]  J. Thornton,et al.  Protein recognition of adenylate: an example of a fuzzy recognition template. , 1996, Journal of molecular biology.

[21]  David M. Rocke,et al.  Predicting ligand binding to proteins by affinity fingerprinting. , 1995, Chemistry & biology.

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

[23]  J. Tainer,et al.  The interdependence of protein surface topography and bound water molecules revealed by surface accessibility and fractal density measures. , 1992, Journal of molecular biology.

[24]  D. Banner,et al.  Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors. , 1994, The Journal of biological chemistry.

[25]  J. Bolin,et al.  Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. II. Environment of bound NADPH and implications for catalysis. , 1982, The Journal of biological chemistry.

[26]  J. Gasteiger,et al.  ITERATIVE PARTIAL EQUALIZATION OF ORBITAL ELECTRONEGATIVITY – A RAPID ACCESS TO ATOMIC CHARGES , 1980 .

[27]  Brian K. Shoichet,et al.  Molecular docking using shape descriptors , 1992 .