In silico classification and virtual screening of maleimide derivatives using projection to latent structures discrimina
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ORIGINAL PAPER
In silico classification and virtual screening of maleimide derivatives using projection to latent structures discriminant analysis (PLS-DA) and hybrid docking Liliana Pacureanu • Luminita Crisan • Alina Bora • Sorin Avram • Ludovic Kurunczi
Received: 15 May 2012 / Accepted: 1 July 2012 Ó Springer-Verlag 2012
Abstract In silico screening algorithms are frequently included in drug discovery programs because a significant number of drug candidates have been detected through structure and ligand-based algorithms. In the current work 337 maleimide derivatives that are inhibitors and noninhibitors of GSK-3a/b were successfully investigated by means of a projection to latent structures discriminant analysis and hybrid docking. These models developed with Dragon (M1) and OpenEye (M2) descriptors are statistically robust (training set M1: R2X = 0.677, R2Y = 0.976, Q2Y = 0.970; M2: R2X = 0.651, R2Y = 0.835, Q2Y = 0.830) and suitably predictive according to Golbraikh–Tropsha external validation criteria (test set M1: R2 = 0.949; M2: R2 = 0.835). The models appropriately explained the structural differences between active and inactive compounds in terms of graph topology, substitutional pattern, and molecular flexibility, and predicted false negatives in PubChem assay 1650. The model M2 showed 73.88 % correct external prediction against 264 active maleimides downloaded from ChEMBL. An evaluation of the key interactions with GSK-3b binding site residues was simulated by hybrid docking. A new virtual screening
Electronic supplementary material The online version of this article (doi:10.1007/s00706-012-0816-3) contains supplementary material, which is available to authorized users. L. Pacureanu L. Crisan (&) A. Bora S. Avram Department of Computational Chemistry, Institute of Chemistry of Romanian Academy, 24 Mihai Viteazul Bvd., 300223 Timisoara, Romania e-mail: [email protected] L. Kurunczi Department of Chemical Physics, Faculty of Pharmacy, University of Medicine and Pharmacy ‘‘Victor Babes’’, 2 Eftimie Murgu Avenue, 300041 Timisoara, Romania
methodology involving equation M2 and hybrid docking was applied to 9,042 maleimide derivatives extracted from PubChem. The model M2 predicted 1,327 active compounds that were subsequently docked into the GSK-3b ATP binding site. Finally 648 compounds were established as hits after the exclusion of previously detected active maleimides. The structural diversity of the new compounds is high demonstrating that the scaffold hopping ability of the current approach is noticeable. Keywords GSK-3 PLS-DA Maleimide Hybrid docking
Introduction Nowadays we are witnessing an increase in the scientific effort directed to drug discovery programs aimed at protein inhibition because the modulation of malfunctioning kinases led to new effective therapies [1]. Glycogen synthase kinase-3 (GSK-3) is a ubiquitous proline-directed serine/threonine protein kinase that is essential for life [2, 3]. GSK-3 occurs in two isoforms, GSK-3a and GSK-3b, that are expresse
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