In Silico Triple Targeting of SARS-CoV-2 3CLᵖʳᵒ, PLᵖʳᵒ, and RdRp by Philippine Antitubercular Natural Products Libraries

Abstract

The global pandemic disease COVID-19 commands a number of host immunological responses to deadly cytokine-storm manifestations. Mitigation of incoming infectious comorbidities ushered by immunosuppression such as tuberculosis (TB) is warranted including the requirement of new drugs. Employment of computational screening methods and intricate selection of putative viral protein targets allows identification of lead mitigating compounds against COVID-19. Antitubercular natural products may offer privileged starting points as potential antagonistic prospects for SARS-CoV-2 non-structural proteins implicated in viral replication and infection mechanisms. In this study, antitubercular natural products from Philippine medicinal plants are repurposed as inhibitors of vital SARS-CoV-2 nsps such as 3CLpro (3-chymotrypsin-like protease), PLpro (papain-like protease), and RdRp (RNA-dependent RNA polymerase) using in silico methods. A total of 67 antitubercular compounds were computationally screened using molecular docking in 3CLpro, PLpro, and RdRp followed by subsequent ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis of top-binding compounds to assess their drug-likeness and pharmacokinetic properties. Based on the results of our molecular docking analysis, 10 antitubercular natural product cocktails exhibited strong binding propensities against 3CLpro, PLpro, and RdRp. Several compounds demonstrated multi- targeting inhibition to at least two vital non-structural proteins (nsps). Vobtusine lactone (1), deoxyvobtusine lactone (6), and deoxyvobtusine (7) exhibited superior target-specific binding while globospiramine (3) was found to be a potential multi-targeting alkaloid with amenable drug-like properties. The study elaborated for the first time, the computational screeningof antitubercular compounds against three vital targets of SARS-CoV-2 yielding potentialdrug-like compounds against COVID-19 infection. A combination of excellent binding scores,dynamic stability, drug-likeness, and pharmacokinetic properties identified vobtusine lactone(1), deoxyvobtusine lactone (6), deoxyvobtusine (7), and the triple targeting globospiramine (3)as promising leads representing new anti-SARS-CoV-2 scaffolds.