J Chem Inf Model - Four-dimensional structure-activity relationship model to predict HIV-1 integrase strand transfer inhibition using LQTA-QSAR methodology.

Tópicos

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Resumo

Despite highly active antiretroviral therapy (HAART) implementation, there is a continuous need to search for new anti-HIV agents. HIV-1 integrase (HIV-1 IN) is a recently validated biological target for AIDS therapy. In this work, a four-dimensional quantitative structure-activity relationship (4D-QSAR) study using the new methodology named LQTA-QSAR approach with a training set of 85 HIV-1 IN strand transfer inhibitors (INSTI), containing the ?-diketo acid (DKA) substructure, was carried out. The GROMACS molecular dynamic package was used to obtain a conformational ensemble profile (CEP) and LQTA-QSAR was employed to calculate Coulomb and Lennard-Jones potentials and to generate the field descriptors. The partial least-squares (PLS) regression model using 14 field descriptors and 8 latent variables (LV) yielded satisfactory statistics (R2= 0.897, SEC = 0.270, and F = 72.827), good performance in internal (QLOO2 = 0.842 and SEV = 0.314) and external prediction (Rpred2 = 0.839, SEP = 0.384, AREpred = 4.942%, k = 0.981, k' = 1.016, and |R02 ? R0'2 = 0.0257). The QSAR model was shown to be robust (leave-N-out cross validation; average QLNO2 = 0.834) and was not built by chance (y-randomization test; R2 intercept = 0.109; Q2 intercept = -0.398). Fair chemical interpretation of the model could be traced, including descriptors related to interaction with the metallic cofactors and the hydrophobic loop. The model obtained has a good potential for aid in the design of new INSTI, and it is a successful example of application of LQTA-QSAR as an useful tool to be used in computer-aided drug design (CADD).

Resumo Limpo

despit high activ antiretrovir therapi haart implement continu need search new antihiv agent hiv integras hiv recent valid biolog target aid therapi work fourdimension quantit structureact relationship dqsar studi use new methodolog name lqtaqsar approach train set hiv strand transfer inhibitor insti contain diketo acid dka substructur carri gromac molecular dynam packag use obtain conform ensembl profil cep lqtaqsar employ calcul coulomb lennardjon potenti generat field descriptor partial leastsquar pls regress model use field descriptor latent variabl lv yield satisfactori statist r sec f good perform intern qloo sev extern predict rpred sep arepr k k r r qsar model shown robust leavenout cross valid averag qlno built chanc yrandom test r intercept q intercept fair chemic interpret model trace includ descriptor relat interact metal cofactor hydrophob loop model obtain good potenti aid design new insti success exampl applic lqtaqsar use tool use computeraid drug design cadd

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