Neuropilin 1 (NRP-1) inhibition has shown promise in reducing the infectivity of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and preventing the virus entry into nerve tissues, thereby mitigating neurological symptoms in COVID-19 patients. In this study, we employed virtual screening, including molecular docking, Molecular Dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculations, to identify potential NRP-1 inhibitors. From a compendium of 1930 drug-like natural compounds, we identified five potential leads: CNP0435132, CNP0435311, CNP0424372, CNP0429647, and CNP0427474, displaying robust binding energies of -8.2, -8.1, -10.7, -8.2, and -8.2 kcal/mol, respectively. These compounds demonstrated interactions with critical residues Tyr297, Trp301, Thr316, Asp320, Ser346, Thr349, and Tyr353 located within the b1 subdomain of NRP-1. Furthermore, MD simulations and MM-PBSA calculations affirmed the stability of the complexes formed, with average root mean square deviation, radius of gyration, and solvent accessible surface area values of 0.118 nm, 1.516 nm, and 88.667 nm2 , respectively. Notably, these lead compounds were estimated to penetrate the blood-brain barrier and displayed antiviral properties, with Pa values ranging from 0.414 to 0.779. The antagonistic effects of these lead compounds merit further investigation, as they hold the potential to serve as foundational scaffolds for the development of innovative therapeutics aimed at reducing the neuroinfectivity of SARS-CoV-2.
Keywords: C-end rule; SARS-CoV-2; molecular docking; molecular dynamics; neuropilin-1.
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