| ORIGINAL RESEARCH ARTICLE
|Year : 2022 | Volume
| Issue : 6 | Page : 431-442
Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R)
Manisha Prajapat1, Phulen Sarma1, Nishant Shekhar1, Arushi Chauhan2, Gurjeet Kaur1, Anusuya Bhattacharyya3, Pramod Avti2, Gajendra Choudhary1, Seema Bansal1, Saurabh Sharma1, Hardeep Kaur4, Subodh Kumar1, Harvinder Mann1, Anupam Raja1, Ashutosh Singh1, Rahul Singh1, Amit Raj Sharma1, Ajay Prakash1, Bikash Medhi1
1 Department of Pharmacology, PGIMER, Chandigarh, India
2 Department of Biophysics, PGIMER, Chandigarh, India
3 Department of Ophthalmology, GMCH, Chandigarh, India
4 Department of Paediatrics, PGIMER, Chandigarh, India
INTRODUCTION: Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein.
MATERIALS AND METHODS: Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
RESULTS AND DISCUSSION: Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better.
CONCLUSION: We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.
Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
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