Showing papers by "Mutasem O. Taha published in 2010"

Pharmacophore and QSAR modeling of estrogen receptor β ligands and subsequent validation and in silico search for new hits

Abstract: The pharmacophoric space of estrogen receptor beta (ERbeta) was explored using a set of 119 known ligands. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combinations of pharmacophoric models and physicochemical descriptors in self-consistent and predictive quantitative structure-activity relationships (QSARs) (r(96)(2)=0.79-0.83, F-statistic=40.96-36.20, r(LOO)(2)=0.74-0.76 and r(PRESS)(2) against 23 external compounds=0.54-0.56, respectively). Four binding hypotheses emerged in two optimal QSAR equations suggesting the existence of distinct binding modes accessible to ligands within ERbeta binding pocket. The close similarity among the resulting pharmacophores prompted us to merge them in two hybrid models. The hybrid pharmacophores illustrated superior receiver operator characteristic curves (ROCs) and closely resembled binding interactions suggested by docking experiments. The resulting models and associated QSAR equations were employed to screen the national cancer institute (NCI) list of compounds and an in house built database of known drugs and agrochemicals to search for new ERbeta ligands.

Elaborate Ligand-Based Modeling Reveals New Nanomolar Heat Shock Protein 90α Inhibitors

Abstract: Heat shock protein (Hsp90α) has been recently implicated in cancer prompting several attempts to discover and optimize new Hsp90α inhibitors. Toward this end, we explored the pharmacophoric space of 83 Hsp90α inhibitors using six diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure−activity relationship (QSAR) of optimal predictive potential (r672 = 0.811, F = 42.8, rLOO2 = 0.748, rPRESS2 (against 16 external test inhibitors) = 0.619). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the Hsp90α binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric model...