ArticleIn silico pharmacology2024
Design and study of bioisosteric analogues of the drug Molnupiravir as potential therapeutics against SARS-COV-2: an in silico approach.
Article in In silico pharmacology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The ongoing SARS-CoV-2 pandemic has created an urgent need for effective antiviral drugs that can be rapidly developed and utilized to treat patients infected with the virus. Molnupiravir, a direct-acting oral antiviral, has shown promising results in reducing viral infections with SARS-CoV-2. Nonetheless, there is still a need for the development of more efficacious analogues with enhanced interaction with the specific target, the RNA dependent RNA polymerase (RdRp) and better physico-chemical profile. Our study is based on a rational design strategy, known as "bioisosterism", to design some analogues. The pool of bioisosteric structural analogues was further enriched using the "SwissBioisostere" database. Only structures with a Tanimoto score more than 0.85 (calculated using the Maximum Common Substructure scoring method) and with ΔlogP (lipophilicity) ± 1 and ΔPSA (Polar Surface Area) ± 10 Å were retained. Next, molecular docking studies were conducted using AutoDock Vina®. Ligand and receptor preparation and molecular interaction analysis were performed using UCSF Chimera® and Biovia Discovery Studio®, respectively. The three-dimensional structure of the RdRp of SARS-CoV-2 (6M71) was sourced from RCSB PDB®. Ligands were prepared in 3D, and the receptor underwent solvent removal, elimination of alternative positions, hydrogen atom addition, and partial charge assignment. Binding pocket coordinates were determined, and utilized for AutoDock Vina® docking. Parallelly, the druglikeness of our molecules was predicted using the website ADME-SWISS: http://www.swissadme.ch/, based on Lipinski and Weber scores. Docking outcomes, combined to druglikeness prediction results, identified two fluorinated analogues with superior binding affinity (lowest score and an RMSD ≤ 2 Å) and improved physico-chemical properties (no violation of Lipinsky and Veber rules). This study contributes to the development of more effective antiviral drugs by providing insights into potential uegs with enhanced interactions with RNA polymerase and better druglikeness profile. Graphical abstract:
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