Molecular basis for drug repurposing to study the interface of the S protein in SARS-CoV-2 and human ACE2 through dockin
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ORIGINAL PAPER
Molecular basis for drug repurposing to study the interface of the S protein in SARS-CoV-2 and human ACE2 through docking, characterization, and molecular dynamics for natural drug candidates Meshari Alazmi 1
&
Olaa Motwalli 2
Received: 18 May 2020 / Accepted: 5 November 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract A novel coronavirus (SARS-CoV-2) identified in Wuhan state of China in 2019 is the causative agent of deadly disease COVID19. It has spread across the globe (more than 210 countries) within a short period. Coronaviruses pose serious health threats to both humans and animals. A recent publication reported an experimental 3D complex structure of the S protein of SARS-CoV-2 showed that the ectodomain of the SARS-CoV-2 S protein binds to the peptidase domain (PD) of human ACE2 with a dissociation constant (Kd) of ~ 15 nM. In this study, we focused on inhibitors for ACE2: S protein complex using virtual screening and inhibition studies through molecular docking for over 200,000 natural compounds. Toxicity analysis was also performed for the best hits, and the final complex structures for four complexes were subjected to 400 ns molecular dynamics simulations for stability testing. We found two natural origin inhibitors for the S protein: human ACE2 complex (Andrographolide and Pterostilbene) which displayed better inhibition potential for ACE2 receptor and its binding with the S protein of SARS-CoV-2. Comparative studies were also performed to test and verify that these two drug candidates are also better than hydroxychloroquine which is known to inhibit this complex. However, we needed better potential drug candidates to overcome the side effects of hydroxychloroquine. Supplementary experimental studies need to be carried forward to corroborate the viability of these two new inhibitors for ACE2: S protein complex so as to curb down COVID-19. Keywords COVID-19 . SARS-CoV-2 . Molecular dynamics . Andrographolide . S protein: human ACE2 complex
Introduction A novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) was subsequently detected in the Wuhan state of China in the last quarter of 2019 as the causative pathogen for the COVID-19 (coronavirus disease 2019), a lethal respiratory tract infection. Genetically this virus closely resembles the SARS virus. It has spread across the globe (more than 210 countries) within a short period. Coronaviruses pose serious health threats to both humans * Meshari Alazmi [email protected] 1
College of Computer Science and Engineering, University of Ha’il, P.O. Box 2440, Ha’il 81411, Kingdom of Saudi Arabia
2
College of Computing and Informatics, Saudi Electronic University (SEU), Madinah 41538-53307, Kingdom of Saudi Arabia
and animals. The mortality rate for 2019-nCoV (novel coronavirus) is not as high (approximately 2–3%), in comparison to SARS-CoV (severe acute respiratory syndrome coronavirus) having fatality rate of ∼ 10% and MERS-CoV (Middle East respiratory syndrome coronavirus) having fa
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