ABSTRACT
Euphorbia hirta L. is a medicinal plant widely used in the Philippines and across tropical Asia against various diseases, including respiratory disorders. In this study, the phytochemical components of E. hirta were investigated in silico for their potential to inhibit the severe acute respiratory syndrome-coronavirus-2 main protease (SARS-CoV-2 Mpro), a coronavirus disease 2019 (COVID-19) drug target that plays a critical role in the infection process of SARS-CoV-2. Phytochemical mining in tandem with virtual screening (PM-VS) was the strategy implemented in this study, which allows efficient preliminary in silico assessment of the COVID-19 therapeutic potential of the reported phytochemicals from the plant. The main rationale for considering E. hirta in the investigation was its reported efficacy against respiratory disorders. It is very promising to investigate the phytochemicals of E. hirta for their potential efficacy against diseases, such as COVID-19, that also target the respiratory system. A total of 298 E. hirta phytochemicals were comprehensively collected from the scientific literature. One hundred seventy of these phytochemicals were computed through molecular docking and were shown to have comparable or better binding properties (promising inhibitors) toward SARS-CoV-2 Mpro than known in vitro inhibitors. In connection to our previous work considering different medicinal plants, antiviral compounds were also rediscovered from the phytochemical composition of E. hirta. This finding provides additional basis for the potential of the plant (or its phytochemicals) as a COVID-19 therapeutic directly targeting drug targets such as SARS-CoV-2 Mpro and/or addressing respiratory-system-related symptoms. The study also highlights the utility of PM-VS, which can be efficiently implemented in the preliminary steps of drug discovery and development.
ABSTRACT
AIM: The prevailing crisis caused by COVID-19 pandemic demands the development of effective therapeutic agents that can be implemented with minimal to zero adverse effects. BACKGROUND: Vitex negundo L. (VNL) is a medicinal plant with reported efficacy against respiratory diseases and some of the COVID-19 symptoms. Funded by the Department of Science and Technology (DOST), the University of the Philippines - Philippine General Hospital (UP-PGH) is currently conducting clinical trials of VNL and other medicinal plants as adjuvant therapeutic agents against mild cases of COVID-19. The basis for the clinical trials is primarily the pharmacological efficacy of the medicinal plants against respiratory disorders and associated COVID-19 symptoms. OBJECTIVE: This study assessed the in silico potential of VNL components against SARS-CoV-2 main protease (Mpro), an enzyme that plays an important role in COVID-19, the disease caused by the SARS-CoV-2. METHOD: Phytochemical mining of VNL components from the literature was conducted. A database consisting of 250 known compounds from different parts of VNL was created and screened against SARS-CoV-2 Mpro using PyRx virtual screening tool. The most promising components were further subjected to in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses using the SwissADME web server and Toxtree software. RESULTS: Virtual screening revealed that 102 VNL components in the database had comparable to or better binding affinities toward SARS-COV-2 Mpro than known chemical inhibitors (e.g. N3 and carmofur). It was determined that the active site of SARS-CoV-2 Mpro receptor consists of multiple H-donor and acceptor sites; hence, the most stable receptor-ligand complexes are generally formed by VNL ligands that establish effective H-bonding with the SARS-CoV-2 Mpro. The promising components, representing a "cocktail" of potential inhibitors also revealed interesting ADMET properties. CONCLUSION: This in silico study identified VNL as a potential single source of a cocktail of SARSCoV- 2 Mpro inhibitors and a promising adjuvant therapeutic agent against COVID-19 or its symptoms. Furthermore, the study offers a rationale on phytochemical mining from medicinal plants as a means that can be implemented in the early stage of a drug discovery and development program.