Coronaviruses   Send Orders for Reprints to reprints@benthamscience.net Coronaviruses, 2021, 2, 89-105 89 RESEARCH ARTICLE Virtual Screening of Potential Therapeutic Inhibitors Against Spike, Heli- case, and Polymerase of SARS-CoV-2 (COVID-19) Ayesha Tazeen 1 , Farah Deeba 1 , Aftab Alam 1 , Rafat Ali 1 , Romana Ishrat 1 , Anwar Ahmed 2,3 , Sher Ali 1 and Shama Parveen 1,* 1 Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India; 2 Centre of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia; 3 Protein Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia A R T I C L E H I S T O R Y Received: May 29, 2020 Revised: July 17, 2020 Accepted: July 18, 2020 DOI: 10.2174/2666796701999200826114306 Abstract: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected around 13 million people and has caused more than 5.7 lakh deaths worldwide since December 2019. In the absence of FDA approved drugs for its treatment, only symptomatic management is done. Methods: We attempted to uncover potential therapeutic targets of spike, helicase, and RNA dependent RNA polymerase (RdRp) proteins of the SARS-CoV-2 employing a computational approach. The PDB structure of spike and RdRp and predicted structure of helicase proteins were docked with 100 approved anti-viral drugs, natural compounds, and some other chemical compounds. Results: The anti-SARS ligands EK1 and CID 23631927, and NCGC00029283 are potential entry in- hibitors as they showed affinity with immunogenic Receptor Binding Domain (RBD) of the spike pro- tein. This RBD interacts with Angiotensin Converting Enzyme (ACE2) receptor, facilitating the entry of virion in the host cells. The FDA approved drugs, including Nelfinavir, Saquinavir, Tipranavir, Setrobu- vir, Indinavir, and Atazanavir, showed potential inhibitory activity against targeted domains and thus, may act as entry or replication inhibitor or both. Furthermore, several anti-HCoV natural compounds, including Amentoflavone, Rutin, and Tannin, are also potential entry and replication inhibitors as they showed affinity with RBD, P-loop containing nucleoside triphosphate hydrolase, and the catalytic do- main of the respective protein. Dithymoquinone showed significant inhibitory potential against the fu- sion peptide of S2 domain. Importantly, Tannin, Dithymoquinone, and Rutin can be extracted from Nig- ella sativa seeds and thus, may prove to be one of the most potential anti-SARS-CoV-2 inhibitors. Conclusion: Several potential ligands were identified with already known anti-HCoVs activities. Fur- thermore, as this study showed that some of the ligands acted as both entry and replication inhibitors against SARS-CoV-2, it is envisaged that a combination of either inhibitor with a dual mode of action would prove to be a much desired therapeutic option against this viral infection. Keywords: SARS-CoV-2, spike, helicase, RdRp, virtual screening, potential inhibitors, drug repurposing, natural compounds 1. INTRODUCTION Coronavirus disease 2019 (COVID-19) is caused by se- vere acute respiratory syndrome Coronavirus-2 (SARS-CoV- 2) of the family Coronaviridea and order Nidovirales. Ini- tially, the SARS-CoV-2 followed the modus operandi of other Coronaviridea family members, such as SARS (2003) and MERS (2012). Later on, unlike SARS and MERS, the SARS-CoV-2 assumed pandemic proposition, causing huge morbidity and mortality across the world [1]. Till July 14, 2020, around 13 million confirmed cases and 5.7 lakh deaths were reported globally with the Case Fatality Rate (CFR) of *Address correspondence to this author at the Centre for Interdisciplinary Research in Basic Sciences Jamia Millia Islamia, New Delhi, India; E-mails: sparveen2@jmi.ac.in; shamp25@yahoo.com 22.51% [2]. Owing to the imperil of such a large scale infec- tion, the World Health Organisation (WHO) declared COVID-19 a pandemic on 11 th March 2020. COVID-19 spreads among people via the respiratory droplets of the in- fected individual’s cough or sneeze. The COVID-19 patients show respiratory symptoms, shortness of breath, cough, fe- ver, and other breathing related difficulties as the lungs are affected. In some cases, the infection can cause severe acute respiratory syndrome, pneumonia, multi-organ failure, and even death [3]. WHO and Centers for Disease Control (CDC) have recommended the use of face mask, mainte- nance of a high level of personal hygiene, including hand wash for at least 30 seconds, and medical help as soon as the symptoms arise. Current therapy for patients include suppor- tive care and social distancing to manage COVID-19 [4]. 2666-7975/21 $65.00+.00 © 2021 Bentham Science Publishers