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Molecules 2018, 23(9), 2141; https://doi.org/10.3390/molecules23092141

Comparative Studies of the Dynamics Effects of BAY60-2770 and BAY58-2667 Binding with Human and Bacterial H-NOX Domains

1
Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 45550, Pakistan
2
College of Informatics, Huazhong Agricultural University (HZAU), Wuhan 430070, China
3
Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
4
Department of Chemistry, College of Sciences and Humanities, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Received: 12 July 2018 / Revised: 11 August 2018 / Accepted: 22 August 2018 / Published: 25 August 2018
(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)
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Abstract

Soluble guanylate cyclase (sGC) is a key enzyme implicated in various physiological processes such as vasodilation, thrombosis and platelet aggregation. The enzyme’s Heme-Nitric oxide/Oxygen (H-NOX) binding domain is the only sensor of nitric oxide (NO) in humans, which on binding with NO activates sGC to produce the second messenger cGMP. H-NOX is thus a hot target for drug design programs. BAY60-2770 and BAY58-2667 are two widely studied activators of sGC. Here we present comparative molecular dynamics studies to understand the molecular details characterizing the binding of BAY60-2770 and BAY58-2667 with the human H-NOX (hH-NOX) and bacterial H-NOX (bH-NOX) domains. HartreeFock method was used for parametrization of both the activators. A 50 ns molecular dynamics (MD) simulation was run to identify the functionally critical regions of the H-NOX domains. The CPPTRAJ module was used for analysis. BAY60-2770 on binding with bH-NOX, triggered rotational movement in signaling helix F and significant dynamicity in loops α and β, but in hH-NOX domain the compound showed relatively lesser aforementioned structural fluctuations. Conversely, hH-NOX ligated BAY58-2667 experienced highest transitions in its helix F due to electrostatic interactions with D84, T85 and R88 residues which are not conserved in bH-NOX. These conformational transformations might be essential to communicate with downstream PAS, CC and cyclase domains of sGC. Comparative MD studies revealed that BAY bound bHNOX dynamics varied from that of hH-NOX, plausibly due to some key residues such as R40, F74 and Y112 which are not conserved in bacteria. These findings will help to the design of novel drug leads to cure diseases associated to human sGC. View Full-Text
Keywords: soluble guanylate cyclase; sGC activator compounds; quantum calculation; molecular dynamics simulation soluble guanylate cyclase; sGC activator compounds; quantum calculation; molecular dynamics simulation
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Rehan Khalid, R.; Tahir ul Qamar, M.; Maryam, A.; Ashique, A.; Anwar, F.; H. Geesi, M.; Siddiqi, A.R. Comparative Studies of the Dynamics Effects of BAY60-2770 and BAY58-2667 Binding with Human and Bacterial H-NOX Domains. Molecules 2018, 23, 2141.

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