Summary
Exploitation of protein structures for potential drug leads by molecular docking is critically dependent on methods for scoring putative protein-ligand interactions. An ideal function for scoring must exhibit predictive accuracy and high computational speed, and must be tolerant of variations in the relative protein-ligand molecular alignment and conformation. This paper describes the development of an empirically derived scoring function, based on the binding affinities of protein-ligand complexes coupled with their crystallographically determined structures. The function's primary terms involve hydrophobic and polar complementarity, with additional terms for entropic and solvation effects. The issue of alignment/conformation dependence was solved by constructing a continuous differentiable nonlinear function with the requirement that maxima in ligand conformation/alignment space corresponded closely to crystallographically determined structures. The expected error in the predicted affinity based on cross-validation was 1.0 log unit. The function is sufficiently fast and accurate to serve as the objective function of a molecular-docking search engine. The function is particularly well suited to the docking problem, since it has spatially narrow maxima that are broadly accessible via gradient descent.
Similar content being viewed by others
References
Rutenber E., Fauman E.B., Keenan R.J., Fong S., Furth P.S., Ortiz de Montellano P.R., Meng E., Kuntz I.D., DeCamp D.L., Salto R., Rose J.R., Craik C.S. and Stroud R.M., J. Biol. Chem., 268 (1993) 15343.
Shoicet B.K., Stroud R.M., Santi D.V., Kuntz I.D. and Perry K.M., Science, 259 (1993) 1445.
Bodian D.L., Yamasaki R.B., Buswell R.L., Stearns J.F., White J.M. and Kuntz I.D., Biochemistry, 32 (1993) 2967.
Ring C.S., Sun E., McKerrow J.H., Lee G.K., Rosenthal P.J., Kuntz I.D. and Cohen F.E., Proc. Natl. Acad. Sci. USA, 90 (1993) 3583.
Jain A.N., Harris N.L. and Park J.Y., J. Med. Chem., 38 (1995) 1295.
Jain A.N., Dietterich T.G., Lathrop R.L., Chapman D., Critchlow R.E., Bauer B.E., Webster T.A. and Lozano-Perez T., J. Comput.-Aided Mol. Design, 8 (1994) 635.
Jain A.N., Koile K. and Chapman D., J. Med. Chem., 37 (1994) 2315.
Böhm H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 243.
Bohacek R.S. and McMartin C., J. Med. Chem., 35 (1992) 1671.
Ruppert, J., Welch, W. and Jain, A.N., manuscript submitted for publication.
Welch W., Ruppert J. and Jain A.N., Chem. Biol., 3 (1996) 449.
Murray-Rust P. and Glusker J.P., J. Am. Chem. Soc., 106 (1984) 1018.
Searle M.S. and Williams D.H., J. Am. Chem. Soc., 114 (1992) 10690.
Weber P.C., Wendoloski J.J., Pantoliano M.W. and Salemme F.R., J. Am. Chem. Soc., 114 (1992) 3197.
Miyamoto S. and Kollman P.A., Proteins, 16 (1993) 226.
Katz B.A., Biochemistry, 34 (1995) 15421.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jain, A.N. Scoring noncovalent protein-ligand interactions: A continuous differentiable function tuned to compute binding affinities. J Computer-Aided Mol Des 10, 427–440 (1996). https://doi.org/10.1007/BF00124474
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00124474