J Chem Inf Model - Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening.

Tópicos

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Resumo

The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of oncogenic signaling proteins. For this reason, Hsp90 has emerged as a promising target for anticancer drug development. Herein, we describe a complete computational procedure for building several 3-D QSAR models used as a ligand-based (LB) component of a comprehensive ligand-based (LB) and structure-based (SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, eight SB PLS 3-D QSAR models were generated, leading to a final multiprobe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for Hsp90 inhibition. Both the monoprobe and multiprobe models were optimized, cross-validated, and tested against an external test set. The obtained statistical results confirmed the models as robust and predictive to be used in a subsequent VS.

Resumo Limpo

multichaperon heat shock protein hsp complex mediat matur stabil varieti oncogen signal protein reason hsp emerg promis target anticanc drug develop herein describ complet comput procedur build sever d qsar model use ligandbas lb compon comprehens ligandbas lb structurebas sb virtual screen vs protocol identifi novel molecular scaffold hsp inhibitor applic d qsautogridr method eight sb pls d qsar model generat lead final multiprob mp d qsar pharmacophor model capabl recogn signific chemic featur hsp inhibit monoprob multiprob model optim crossvalid test extern test set obtain statist result confirm model robust predict use subsequ vs

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