Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5

International Journal of Molecular Sciences
Fangfang YanJianzhong Chen

Abstract

Designing highly selective inhibitors of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is of importance for treatment of some diseases related with inflammation, metabolism, and tumor growth. In this study, molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method were performed to probe binding selectivity of three inhibitors (5M7, 65X, and 65Z) to FABP4/FABP5 with Ki values of 0.022/0.50 μM, 0.011/0.086 μM, and 0.016/0.12 μM, respectively. The results not only suggest that all inhibitors associate more tightly with FABP4 than FABP5, but also prove that the main forces driving the selective bindings of inhibitors to FABP4 and FABP5 stem from the difference in the van der Waals interactions and polar interactions of inhibitors with two proteins. Meanwhile, a residue-based free energy decomposition method was applied to reveal molecular basis that inhibitors selectively interact with individual residues of two different proteins. The calculated results show that the binding difference of inhibitors to the residues (Phe16, Phe19), (Ala33, Gly36), (Phe57, Leu60), (Ala75, Ala78), (Arg126, Arg129), and (Tyr128, Tyr131) in (FABP4, FABP5) drive the selectivity of inhib...Continue Reading

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Citations

Oct 2, 2019·Physical Chemistry Chemical Physics : PCCP·Shuaizhen TianTong Zhu
May 26, 2020·Journal of Biomolecular Structure & Dynamics·Yanis R EspinosaC Manuel Carlevaro
Mar 2, 2019·Journal of Clinical Medicine·Jolanta Patro-MałyszaBożena Leszczyńska-Gorzelak
Jul 9, 2020·Computational and Structural Biotechnology Journal·Fangfang Yan, Feng Gao
Aug 20, 2019·Bioorganic & Medicinal Chemistry·Yulong HeYingxia Li
Aug 24, 2019·Computational Biology and Chemistry·Priya Kumari, Raju Poddar
Feb 23, 2019·Journal of Agricultural and Food Chemistry·Xiao-Lei ZhuGuang-Fu Yang
Dec 24, 2021·Journal of Biomolecular Structure & Dynamics·Nishi Prakash TiwariDev Mani Pandey

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Software Mentioned

CPPTRAJ
VMD
PyMOL
FF99SB
MM
GBSA
AM1
Amber
AutoDock4

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