Rescoring of docking poses under Occam's Razor: are there simpler solutions?

Journal of Computer-aided Molecular Design
Michael ZheninDragos Horvath

Abstract

Ligand affinity prediction from docking simulations is usually performed by means of highly empirical and diverse protocols. These protocols often involve the re-scoring of poses generated by a force field (FF) based Hamiltonian to provide either estimated binding affinities-or alternatively, some empirical goodness score. Re-scoring is performed by so-called scoring functions-typically, a reweighted sum of FF terms augmented by additional terms (e.g., desolvation/entropic penalty, hydrophobicity, aromatic interactions etc.). Sometimes, the scoring function actually drives ligand positioning, but often it only operates on the best scoring poses ranked top by the initial ligand positioning tool. In either of these rather intricate scenarios, scoring functions are docking-specific models, and most require machine-learning-based calibration. Therefore, docking simulations are less straightforward when compared to "standard" molecular simulations in which the FF Hamiltonian defines the energy, and affinity emerges as an ensemble average property over pools of representative conformers (i.e., the trajectory). Paraphrasing on Occam's Razor principle, additional model complexity is only acceptable if demonstrated to bring a significan...Continue Reading

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Citations

Jun 21, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dragos HorvathAlexandre Varnek
Apr 21, 2020·Physical Chemistry Chemical Physics : PCCP·David I Ramírez-PalmaFernando Cortés-Guzmán
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Apr 17, 2021·Journal of Chemical Information and Modeling·Francois BerengerYoshihiro Yamanishi
Aug 14, 2020·Journal of Chemical Information and Modeling·Natesh SinghBruno O Villoutreix
May 7, 2020·Journal of Chemical Information and Modeling·Dragos HorvathAlexandre Varnek
Feb 21, 2019·Journal of Chemical Information and Modeling·Boris SattarovAlexandre Varnek
Nov 16, 2019·Current Medicinal Chemistry·Gabriela Bitencourt-FerreiraWalter Filgueira de Azevedo

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