Molecular Docking suggests repurposing of Brincidofovir as a potential drug targeting SARS-CoV-2 "COVID-19" ACE2 receptor and main protease

Hussien, Mostafa A.; Abdelaziz, Ahmed E. M.

doi:10.21203/rs.3.rs-35787/v1

Cited by 1 publication

(1 citation statement)

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“…The compounds that showed the most favorable binding profile and the best binding scores were shortlisted in Table 1. 29,30 From the initial hits 13 were identified that showed consistent good binding scores and binding poses. The compounds shortlisted bound to the protein-protein interface, and established interactions with key residues namely, His34, Asp38, and Lys353 from the ACE-2 binding region and Lys417, Gly496 and Tyr505 from the S-RBD.…”

Section: Docking Studiesmentioning

confidence: 99%

In silico drug repurposing using molecular docking and dynamics to target the protein interaction between the SARS-CoV-2 S-glycoprotein and the ACE2 receptor

Hussein,

Almatrafi,

Gomaa

et al. 2023

F1000Res

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Background: The protein interaction between the viral surface S-glycoprotein and the host angiotensin converting enzyme-2 receptor (ACE2) is key to the virulent nature of SARS-CoV-2. The potential role that effective drug repurposing strategies may have to help stem the impact of future outbreaks has been brought to light in the recent COVID-19 pandemic. This study outlines a comprehensive approach towards in-silico drug discovery which aims to identify hit agents that can be suitably translated into a clinical setting. Methods: We use two different computational platforms to analyze the viral S-glycoprotein in its bound conformational state to the ACE2 receptor. We employed a comprehensive screening approach to shortlist compounds capable of binding to the viral target interface and corroborated these findings using both Schrödinger’s Glide and AutoDock Vina. Molecular dynamic simulation studies further verified the stability of the interaction at the viral-host protein interface. Results: Lymecycline, pentagalloylglucose, polydatin, and hexoprenaline were identified as prime candidates for further studies given the robust and stable nature of their interaction at the viral-host interface and relevance for clinical testing. These agents were shown in a 100-nanosecond simulation trajectory to favorably disrupt key binding interactions at the viral-host interface and may potentially inhibit viral entry into host cells. In all hit molecules it was observed that inhibiting the interaction with the following key viral binding residues: Lys17, Gly496, Tyr 505, and key host residues: His34, Asp38, Lys353, played a critical role toward the inhibition of the viral-host protein interaction. Conclusions: Our study is unique in its comprehensive approach to identify agents that can bind to the S-glycoprotein-ACE2 interface using multiple computational platforms. Among the hit compounds shortlisted in this study, both lymecycline and hexoprenaline may be considered as candidates for preliminarily clinical studies to assess their therapeutic potential in the management of COVID-19 infections.

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Section: Docking Studiesmentioning

confidence: 99%