Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities

Journal of Computer-aided Molecular Design
A N Jain

Abstract

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 ha...Continue Reading

References

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Citations

Mar 1, 1997·Protein Science : a Publication of the Protein Society·J RuppertA N Jain
Sep 28, 2013·Journal of Molecular Modeling·Yingtao LiuWeiliang Zhu
Oct 19, 2005·Journal of Computer-aided Molecular Design·Claudia MachicadoJavier Sancho
Dec 14, 2007·Journal of Computer-aided Molecular Design·Ajay N Jain
Feb 15, 2008·Journal of Computer-aided Molecular Design·Tuan A Pham, Ajay N Jain
Aug 20, 2010·Journal of Computer-aided Molecular Design·Ajay N Jain
Dec 14, 2011·Journal of Computer-aided Molecular Design·Robert D Clark, Marvin Waldman
Dec 22, 2011·Journal of Computer-aided Molecular Design·Ajay N Jain, Ann E Cleves
May 10, 2012·Journal of Computer-aided Molecular Design·Russell Spitzer, Ajay N Jain
Nov 12, 2013·Journal of Computer-aided Molecular Design·Rocco VarelaAjay N Jain
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