Cargando…

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

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 Bor...

Descripción completa

Detalles Bibliográficos
Autores principales: Yan, Fangfang, Liu, Xinguo, Zhang, Shaolong, Su, Jing, Zhang, Qinggang, Chen, Jianzhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164837/
https://www.ncbi.nlm.nih.gov/pubmed/30142969
http://dx.doi.org/10.3390/ijms19092496
_version_ 1783359695273066496
author Yan, Fangfang
Liu, Xinguo
Zhang, Shaolong
Su, Jing
Zhang, Qinggang
Chen, Jianzhong
author_facet Yan, Fangfang
Liu, Xinguo
Zhang, Shaolong
Su, Jing
Zhang, Qinggang
Chen, Jianzhong
author_sort Yan, Fangfang
collection PubMed
description 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 K(i) 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 inhibitors toward FABP4 and FABP5. This study will provide great help for further design of effective drugs to protect against a series of metabolic diseases, arteriosclerosis, and inflammation.
format Online
Article
Text
id pubmed-6164837
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-61648372018-10-10 Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5 Yan, Fangfang Liu, Xinguo Zhang, Shaolong Su, Jing Zhang, Qinggang Chen, Jianzhong Int J Mol Sci Article 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 K(i) 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 inhibitors toward FABP4 and FABP5. This study will provide great help for further design of effective drugs to protect against a series of metabolic diseases, arteriosclerosis, and inflammation. MDPI 2018-08-23 /pmc/articles/PMC6164837/ /pubmed/30142969 http://dx.doi.org/10.3390/ijms19092496 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yan, Fangfang
Liu, Xinguo
Zhang, Shaolong
Su, Jing
Zhang, Qinggang
Chen, Jianzhong
Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5
title Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5
title_full Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5
title_fullStr Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5
title_full_unstemmed Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5
title_short Molecular Dynamics Exploration of Selectivity of Dual Inhibitors 5M7, 65X, and 65Z toward Fatty Acid Binding Proteins 4 and 5
title_sort molecular dynamics exploration of selectivity of dual inhibitors 5m7, 65x, and 65z toward fatty acid binding proteins 4 and 5
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164837/
https://www.ncbi.nlm.nih.gov/pubmed/30142969
http://dx.doi.org/10.3390/ijms19092496
work_keys_str_mv AT yanfangfang moleculardynamicsexplorationofselectivityofdualinhibitors5m765xand65ztowardfattyacidbindingproteins4and5
AT liuxinguo moleculardynamicsexplorationofselectivityofdualinhibitors5m765xand65ztowardfattyacidbindingproteins4and5
AT zhangshaolong moleculardynamicsexplorationofselectivityofdualinhibitors5m765xand65ztowardfattyacidbindingproteins4and5
AT sujing moleculardynamicsexplorationofselectivityofdualinhibitors5m765xand65ztowardfattyacidbindingproteins4and5
AT zhangqinggang moleculardynamicsexplorationofselectivityofdualinhibitors5m765xand65ztowardfattyacidbindingproteins4and5
AT chenjianzhong moleculardynamicsexplorationofselectivityofdualinhibitors5m765xand65ztowardfattyacidbindingproteins4and5