Publication date: Sep 21, 2023

The emergence and immune evasion ability of SARS-CoV-2 Omicron strains, mainly BA. 5.2 and BF. 7 and other variants of concern have raised global apprehensions. With this context, the discovery of multitarget inhibitors may be proven more comprehensive paradigm than its one-drug-to-one target counterpart. In the current study, a library of 271 phytochemicals from 25 medicinal plants from the Indian Himalayan Region has been virtually screened against SARS-CoV-2 by targeting nine virus proteins, viz. , papain-like protease, main protease, nsp12, helicase, nsp14, nsp15, nsp16, envelope, and nucleocapsid for screening of a multi-target inhibitor against the viral replication. Initially, 94 phytochemicals were screened by a hybrid machine learning model constructed by combining 6 confirmatory bioassays against SARS-CoV-2 replication using an instance-based learner lazy k-nearest neighbour classifier. Further, 25 screened compounds with excellent drug-like properties were subjected to molecular docking. The phytochemical Cepharadione A from the plant Piper longum showed binding potential against four proteins with the highest binding energy of -10. 90 kcal/mol. The compound has acceptable absorption, distribution, metabolism, excretion, and toxicity properties and exhibits stable binding behaviour in terms of root mean square deviation (0. 068 +/- 0. 05 nm), root-mean-square fluctuation, hydrogen bonds, solvent accessible surface area (83. 88-161. 89 nm), and molecular mechanics Poisson-Boltzmann surface area during molecular dynamics simulation of 200 ns with selected target proteins. Concerning the utility of natural compounds in the therapeutics formulation, Cepharadione A could be further investigated as a remarkable lead candidate for the development of therapeutic drugs against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

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