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Molecules 2018, 23(7), 1527; https://doi.org/10.3390/molecules23071527

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches

1
Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad 45550, Pakistan
2
Department of Chemistry, Science and Arts College, Rabigh Campus, King Abdulaziz University, Jeddah 21577, Saudi Arabia
3
Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan
4
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
5
Department of Chemistry, University of Agriculture, Faisalabad 38040, Pakistan
*
Author to whom correspondence should be addressed.
Received: 17 May 2018 / Revised: 15 June 2018 / Accepted: 18 June 2018 / Published: 25 June 2018
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
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Abstract

The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r2), leave-one-out (LOO) cross validated correlation coefficient (q2), bootstrapping, and Fisher’s randomization test. The highly reliable and predictive CoMFA (q2 = 0.569, r2 = 0.979) and CoMSIA (q2 = 0.500, r2 = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein’s active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds. View Full-Text
Keywords: BRD4 protein inhibitors; molecular docking; 3D-QSAR; CoMFA; CoMSIA BRD4 protein inhibitors; molecular docking; 3D-QSAR; CoMFA; CoMSIA
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Tahir, A.; Alharthy, R.D.; Naseem, S.; Mahmood, N.; Ahmed, M.; Shahzad, K.; Akhtar, M.N.; Hameed, A.; Sadiq, I.; Nawaz, H.; Muddassar, M. Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches. Molecules 2018, 23, 1527.

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