https://orcid.org/0000-0003-4607-8391
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Abstract
The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate need for potent drugs. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is considered a potential target for drug development. In this study, around 5,800 molecules were virtually screened using molecular docking. Five molecules were selected for in vitro experiments from those that reported docking scores lower than −6 kcal/mol. Imatinib, a Bcr-Abl tyrosine kinase inhibitor, showed maximum antiviral activity in Vero cells. We further investigated the interaction of imatinib, a compound under clinical trials for the treatment of COVID-19, with SARS-CoV-2 RBD, using in silico methods. Molecular dynamics simulations verified that imatinib interacts with RBD residues that are critical for ACE2 binding. This study also provides significant molecular insights on potential repurposable small-molecule drugs and chemical scaffolds for the development of novel drugs targeting the SARS-CoV-2 spike RBD.
Communicated by Ramaswamy H. Sarma
Acknowledgements
We gratefully acknowledge the support from Texas A&M High Performance Research Computing (HPRC) and TAMU Laboratory for Molecular Simulation (LMS). We would like to thank Dr. Lisa Perez (Associate Director for Advanced Computing Enablement, HPRC TAMU) for guidance with MD simulations. We are thankful to Mart Lammers for allowing us to use the fusion assays.
Author contributions
SF, BM, and DR conceived and designed the study. First author NM designed the computational experiments, compiled and analyzed data, and wrote the manuscript. Co-first author HW conducted in silico experiments and compiled figures. SM did a literature review on the resulting compounds and compiled the manuscript. BM performed virology experiments. SF directed and verified studies and authored the manuscript. All authors reviewed and edited the paper.
Code availability
The python script ‘ELIXIR-A-Vina-Batch-Screening-Module’ used for running docking jobs in batch mode has been deposited in GitHub and will be made public upon publication of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the authors.