Screening Virtual ACE2 Enzyme Inhibitory Activity of Compounds for COVID-19 Treatment Based on Molecular Docking
Authors: Thanh Tung Bui , Hong Minh Phạm , Nhu Son Nguyen , The Hai Pham 
Published: December 2020

This study uses an in silico screening docking model to evaluate the ACE2 inhibitory activity of natural compounds and drugs. The study collected 49 compounds and evaluated the ACE2 inhibitory effect in silico. The study results show that 11 out of the 49 compounds had stronger inhibitory activity on ACE2 than MLN-4760. Lipinski’s rule of five criteria and predictive pharmacokinetic-toxicity analysis show that eight compounds including quercetin, galangin, quisinostat, fluprofylline, spirofylline, RS 504393, TNP and GNF-5 had drug-likeness. These compounds could be potential drug for the Covid-19 treatment.
Keywords
SARS-CoV-2S, Covid-19, ACE2, molecular docking, in silico.
References
[[1] C. Wang, P.W. Horby, F.G. Hayden, G.F. Gao. A novel coronavirus outbreak of global health concern. The Lancet 395(10223) (2020) 470.[2] WHO. WHO Coronavirus Disease (COVID-19) Dashboard. WHO, 2020.[3] N. Chen, M. Zhou, X. Dong, J. Qu, F. Gong, Y. Han, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet 395(10223) (2020) 507.[4] J. Yang, Y. Zheng, X. Gou, K. Pu, Z. Chen, Q. Guo, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. International Journal of Infectious Diseases 94 (2020) 91.[5] R. Lu, X. Zhao, J. Li, P. Niu, B. Yang, H. Wu, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet 395(10224) (2020) 565.[6] R. Hilgenfeld. From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. The FEBS journal 281(18) (2014) 4085.[7] D. Wrapp, N. Wang, K.S. Corbett, J.A. Goldsmith, C.L. Hsieh, O. Abiona, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, NY) 367(6483) (2020) 1260.[8] P.A. Rota, M.S. Oberste, S.S. Monroe, W.A. Nix, R. Campagnoli, J.P. Icenogle, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science (New York, NY) 300(5624) (2003) 1394.[9] M. Donoghue, F. Hsieh, E. Baronas, K. Godbout, M. Gosselin, N. Stagliano, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation research 87(5) (2000) E1.[10] H. Zhang, Z. Kang, H. Gong, D. Xu, J. Wang, Z. Li, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv (2020) 2020.01.30.927806.[11] Y. Zhao, Z. Zhao, Y. Wang, Y. Zhou, Y. Ma, W. Zuo. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv (2020) 2020.01.26.919985.[12] E.I. Bahbah, A. Negida, M.S. Nabet. Purposing Saikosaponins for the treatment of COVID-19. Med Hypotheses 140 (2020) 109782.[13] I.W. Cheung, S. Nakayama, M.N. Hsu, A.G. Samaranayaka, E.C. Li-Chan. Angiotensin-I converting enzyme inhibitory activity of hydrolysates from oat (Avena sativa) proteins by in silico and in vitro analyses. Journal of agricultural and food chemistry 57(19) (2009) 9234.[14] T. Joshi, T. Joshi, P. Sharma, S. Mathpal, H. Pundir, V. Bhatt, et al. In silico screening of natural compounds against COVID-19 by targeting Mpro and ACE2 using molecular docking. European review for medical and pharmacological sciences 24(8) (2020) 4529.[15] S. Shahid, A. Kausar, M. Khalid, S. Tewari, T. Alghassab, T. Acar, et al. analysis of binding properties of angiotensin-converting enzyme 2 through in silico molecular docking, 2018.[16] K. Teralı, B. Baddal, H.O. Gülcan. Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment. J Mol Graph Model 100 (2020) 107697.[17] M. Muchtaridi, M. Fauzi, N.K. Khairul Ikram, A. Mohd Gazzali, H.A. Wahab. Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2. Molecules 25(17) (2020) 3980.[18] M.J. Huentelman, J. Zubcevic, J.A. Hernández Prada, X. Xiao, D.S. Dimitrov, M.K. Raizada, et al. Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor. Hypertension (Dallas, Tex : 1979) 44(6) (2004) 903.[19] S. Choudhary, Y.S. Malik, S. Tomar. Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach. Front Immunol 11((2020) 1664.[20] C.A. Lipinski. Lead-and drug-like compounds: the rule-of-five revolution. Drug Discovery Today: Technologies 1(4) (2004) 337.[21] B. Jayaram, T. Singh, G. Mukherjee, A. Mathur, S. Shekhar, V. Shekhar, Eds. Sanjeevini: a freely accessible web-server for target directed lead molecule discovery. Proceedings of the BMC bioinformatics; 2012. Springer (Year).[22] D.E. Pires, T.L. Blundell, D.B. Ascher. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of medicinal chemistry 58(9) (2015) 4066.[23] P. Towler, B. Staker, S.G. Prasad, S. Menon, J. Tang, T. Parsons, et al. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. The Journal of biological chemistry 279(17) (2004) 17996.[24] N.A. Dales, A.E. Gould, J.A. Brown, E.F. Calderwood, B. Guan, C.A. Minor, et al. Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors. Journal of the American Chemical Society 124(40) (2002) 11852.[25] P. Pandey, J.S. Rane, A. Chatterjee, A. Kumar, R. Khan, A. Prakash, et al. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. Journal of Biomolecular Structure and Dynamics (2020) 1.[26] C.A. Lipinski. Lead- and drug-like compounds: the rule-of-five revolution. Drug discovery today Technologies 1(4) (2004) 337.[27] R.O. Barros, F.L. Junior, W.S. Pereira, N.M. Oliveira, R.M. Ramos. Interaction of drug candidates with various SARS-CoV-2 receptors: An in silico study to combat COVID-19. Journal of Proteome Research (2020).