Are <i>Tetrapleura tetraptera</i> Phytochemicals Druggable Against SARS‐CoV‐2 Papain‐Like Protein? A Computational Approach

SARS‐CoV2 Omicron and its substrains are still a critical global health issue and extremely contagious, even with widespread vaccination efforts. Hospitalizations and mortality rates linked to these variants are still prevalent. Current therapeutic options face challenges, including low effectiveness, suboptimal pharmacokinetics, and drug resistance, highlighting the urgent need for alternative treatments. Plants and their phytochemicals offer promising characteristics for developing antiviral agents. This study aimed to explore the virucidal potential of Tetrapleura tetraptera against SARS‐CoV‐2. Specifically, it focused on identifying the phytochemicals in T. tetraptera that hinder the action of SARS‐CoV‐2′s papain‐like protease (PL pro ), a protein that is highly conserved across coronavirus species. Computer‐aided molecular docking and predictive in silico ADMET profiling were employed to evaluate the phytochemicals of T. tetraptera as potential ligands and PL pro (6WRH) as the target. Thirteen screened compounds were successfully docked (including 1,1‐diphenyl‐2‐picrylhydrazyl, alpha‐L‐sorbopyranose, betulinic acid, D‐fructose, diisooctyl phthalate, laminitol, luteolin, myristynoyl, heptanediamide, N , N ′‐di‐benzoyloxy‐, naringenin, stigmasterol, sucrose, and tannin). Among these, eight compounds (1,1‐diphenyl‐2‐picrylhydrazyl, alpha‐L‐sorbopyranose, D‐fructose, laminitol, luteolin, heptanediamide, N , N ′‐di‐benzoyloxy‐, naringenin, and sucrose) exhibited significant binding interactions with PL pro , displaying docking scores between −5 and −9.1 kcal/mol. Most phytocompounds displayed concerning issues (potential mutagens and carcinogens with poor pharmacokinetic profiles) besides heptanediamide, N , N ′‐di‐benzoyloxy‐, which stood out as a good fit for the development of a drug candidate that could target coronavirus PL pro because (i) it was found not to be a Pgp substrate, (ii) its toxicologic profile was also relatively good (slightly neurotoxic with an estimated LD50 of 1000 mg/kg), (iii) it displayed a high gastrointestinal absorption profile and a good synthetic accessibility (1.21), and (iv) it was found not to inhibit any of the cytochromes. Therefore, this investigation serves as a foundation for further in vitro and in vivo evaluations of these phytochemicals to confirm the in silico findings against SARS‐CoV‐2 PL pro .