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Identification of potential SARS-CoV-2 entry inhibitors by targeting the interface region between the spike RBD and human ACE2.
J Infect Public Health. 2021 Feb; 14(2):227-237.JI

Abstract

Coronavirus disease 2019 (COVID-19) is a fatal infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus infection is initiated upon recognition and binding of the spike (S) protein receptor-binding domain (RBD) to the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between S protein and ACE2 receptor is a novel approach to prevent the viral entry into the host cell. The present study is aimed at the identification of small molecules which can disrupt the interaction between SARS-CoV-2 S protein and human ACE2 receptor by binding to the interface region. A chemical library consisting of 1,36,191 molecules were screened for drug-like compounds based on Lipinski's rule of five, Verber's rule and in silico toxicity parameters. The filtered drug-like molecules were next subjected to molecular docking in the interface region of RBD. The best three hits viz; ZINC64023823, ZINC33039472 and ZINC00991597 were further taken for molecular dynamics (MD) simulation studies and binding free energy evaluations using Molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) and Molecular mechanics-Generalized Born surface area (MM-GBSA). The protein-ligand complexes showed stable trajectories throughout the simulation time. ZINC33039472 exhibited binding free energy value lower as compared to the control (emodin) with a higher contribution by gas-phase energy and van der Waals energy to the total binding free energy. Thus, ZINC33039472 is identified to be a promising interfacial binding molecule which can inhibit the interaction between the viral S protein and human ACE2 receptor which would consequently help in the management of the disease.

Authors+Show Affiliations

Department of Basic Sciences and Social Sciences, North-Eastern Hill University, Shillong, 793022, Meghalaya, India. Electronic address: arunbgurung@gmail.com.Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.Department of Environment and Forest Resources, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea.Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33493919

Citation

Gurung, Arun Bahadur, et al. "Identification of Potential SARS-CoV-2 Entry Inhibitors By Targeting the Interface Region Between the Spike RBD and Human ACE2." Journal of Infection and Public Health, vol. 14, no. 2, 2021, pp. 227-237.
Gurung AB, Ali MA, Lee J, et al. Identification of potential SARS-CoV-2 entry inhibitors by targeting the interface region between the spike RBD and human ACE2. J Infect Public Health. 2021;14(2):227-237.
Gurung, A. B., Ali, M. A., Lee, J., Farah, M. A., & Al-Anazi, K. M. (2021). Identification of potential SARS-CoV-2 entry inhibitors by targeting the interface region between the spike RBD and human ACE2. Journal of Infection and Public Health, 14(2), 227-237. https://doi.org/10.1016/j.jiph.2020.12.014
Gurung AB, et al. Identification of Potential SARS-CoV-2 Entry Inhibitors By Targeting the Interface Region Between the Spike RBD and Human ACE2. J Infect Public Health. 2021;14(2):227-237. PubMed PMID: 33493919.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of potential SARS-CoV-2 entry inhibitors by targeting the interface region between the spike RBD and human ACE2. AU - Gurung,Arun Bahadur, AU - Ali,Mohammad Ajmal, AU - Lee,Joongku, AU - Farah,Mohammad Abul, AU - Al-Anazi,Khalid Mashay, Y1 - 2020/12/21/ PY - 2020/09/16/received PY - 2020/11/04/revised PY - 2020/12/08/accepted PY - 2021/1/26/pubmed PY - 2021/3/3/medline PY - 2021/1/25/entrez KW - ACE2 KW - Angiotensin-converting enzyme 2 KW - COVID-19 KW - Molecular docking KW - Molecular dynamics simulation KW - Protein–protein interface KW - RBD KW - Receptor-binding domain KW - SARS-CoV-2 KW - Spike protein SP - 227 EP - 237 JF - Journal of infection and public health JO - J Infect Public Health VL - 14 IS - 2 N2 - Coronavirus disease 2019 (COVID-19) is a fatal infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus infection is initiated upon recognition and binding of the spike (S) protein receptor-binding domain (RBD) to the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between S protein and ACE2 receptor is a novel approach to prevent the viral entry into the host cell. The present study is aimed at the identification of small molecules which can disrupt the interaction between SARS-CoV-2 S protein and human ACE2 receptor by binding to the interface region. A chemical library consisting of 1,36,191 molecules were screened for drug-like compounds based on Lipinski's rule of five, Verber's rule and in silico toxicity parameters. The filtered drug-like molecules were next subjected to molecular docking in the interface region of RBD. The best three hits viz; ZINC64023823, ZINC33039472 and ZINC00991597 were further taken for molecular dynamics (MD) simulation studies and binding free energy evaluations using Molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) and Molecular mechanics-Generalized Born surface area (MM-GBSA). The protein-ligand complexes showed stable trajectories throughout the simulation time. ZINC33039472 exhibited binding free energy value lower as compared to the control (emodin) with a higher contribution by gas-phase energy and van der Waals energy to the total binding free energy. Thus, ZINC33039472 is identified to be a promising interfacial binding molecule which can inhibit the interaction between the viral S protein and human ACE2 receptor which would consequently help in the management of the disease. SN - 1876-035X UR - https://www.unboundmedicine.com/medline/citation/33493919/Identification_of_potential_SARS_CoV_2_entry_inhibitors_by_targeting_the_interface_region_between_the_spike_RBD_and_human_ACE2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1876-0341(20)30770-X DB - PRIME DP - Unbound Medicine ER -