J Chem Inf Model - Comparison of virtual high-throughput screening methods for the identification of phosphodiesterase-5 inhibitors.

Tópicos

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Resumo

Reliable and effective virtual high-throughput screening (vHTS) methods are desperately needed to minimize the expenses involved in drug discovery projects. Here, we present an improvement to the negative image-based (NIB) screening: the shape, the electrostatics, and the solvation state of the target protein's ligand-binding site are included into the vHTS. Additionally, the initial vHTS results are postprocessed with molecular mechanics/generalized Born surface area (MMGBSA) calculations to estimate the favorability of ligand-protein interactions. The results show that docking produces very good early enrichment for phosphodiesterase-5 (PDE-5); however, in general, the NIB and the ligand-based screening performed better with or without the added electrostatics. Furthermore, the postprocessing of the NIB screening results using MMGBSA calculations improved the early enrichment for the PDE-5 considerably, thus, making hit discovery affordable.

Resumo Limpo

reliabl effect virtual highthroughput screen vhts method desper need minim expens involv drug discoveri project present improv negat imagebas nib screen shape electrostat solvat state target protein ligandbind site includ vhts addit initi vhts result postprocess molecular mechanicsgener born surfac area mmgbsa calcul estim favor ligandprotein interact result show dock produc good earli enrich phosphodiesteras pde howev general nib ligandbas screen perform better without ad electrostat furthermor postprocess nib screen result use mmgbsa calcul improv earli enrich pde consider thus make hit discoveri afford

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