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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which causes coronavirus disease-19 (COVID-19) has caused more than 2 million deaths around the globe. The high transmissibility rate of the disease is related to the strong interaction between the virus spike receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) as documented in several reports. In this study, using state-of-the-art computational methods, natural products were screened and their molecular mechanism to disrupt spike RBD-ACE2 recognition was evaluated. There is the sensitivity of results to receptor ensemble docking calculations. Binding free energy and MD simulation are important tools to evaluate the thermodynamics of binding stability and the capacity of top hits to disrupt RBD-ACE2 recognition. The free energy profiles provide a slight decrease in binding affinity of the virus-receptor interaction. Three flavonoids parvisoflavone B (3), alpinumisoflavone (5) and norisojamicin (2) were effective in blocking the viral entry by binding strongly at the spike RBD-ACE2 interface with the inhibition constant of 0.56, 0.78 and 0.93 μM, respectively. The same compounds demonstrated similar effect on free ACE2 protein. Compound (2), also demonstrated ability to bind strongly on free spike RBD. Well-tempered metadynamics established that parvisoflavone B (3) works by binding to three sites namely interface α, β and loop thereby inhibiting viral cell entry. Owing to their desirable pharmacokinetic properties, the presented top hit natural products are suggested for further SARS-COV-2 molecular targets and subsequent in vitro and in vivo evaluations.

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As the coronavirus disease 19 (COVID-19) pandemic continues to pose a health and economic crisis worldwide, the quest for drugs and/or vaccines against the virus continues. The human transmembrase protease serines 2 (TMPRSS2) has attracted attention as a target for drug discovery, as inhibition of its catalytic reaction would results in the inactivation of the proteolytic cleavage of the SARS-CoV-2 S protein. As a result, the inactivation prevents viral cell entry to the host’s cell. In this work, we screened and identified two potent molecules that interact and inhibit the catalytic reaction by using computational approaches. Two docking screening experiments were performed utilizing the crystal structure and holo ensemble structure obtained from molecular dynamics in bound form. There is enhancement and sensitivity of docking results to the holo ensemble as compared to the crystal structure. Compound 1 binds more stable than nafamostat by interacting with catalytic triad residue His296 and Ser441, thereby disrupting the already establish hydrogen bond interaction. The stability of the ligand-TMPRSS2 complexes was studied by molecular dynamics simulation, and the binding energy was re-scored by using MM-PBSA binding free energy. The obtained compounds may serve as initial point towards the discovery of potent TMPRSS2 inhibitors upon further in vivo validation.