Integrated Computational Biophysics approach for Drug Discovery against Nipah Virus

Abstract

The Nipah virus (NiV) poses a pressing global threat to public health due to its high mortality rate, multiple modes of transmission, and lack of effective treatments. NiV glycoprotein G (NiV-G) emerges as a promising target for NiV drug discovery due to its essential role in viral entry and membrane fusion. Therefore, in this study we applied an integrated computational and biophysics approach to identify potential inhibitors of NiV-G within a curated dataset of Peruvian phytochemicals. Our virtual screening results indicated that these compounds could represent a natural source of potential NiV-G inhibitors with {Delta}G values ranging from -8 to -11 kcal/mol. Among them, Procyanidin B2, B3, B7, and C1 exhibited the highest binding affinities and formed the most molecular interactions with NiV-G. Molecular dynamics simulations revealed the induced-fit mechanism of NiV-G pocket interaction with these procyanidins, primarily driven by its hydrophobic nature. Non-equilibrium free energy calculations were employed to determine binding affinities, highlighting Procyanidin B3 and B2 as the ligands with the most substantial interactions. Overall, this work underscores the potential of Peruvian phytochemicals, particularly procyanidins B2, B3, B7, and C1, as lead compounds for developing anti-NiV drugs through an integrated computational biophysics approach. Key pointsO_LINipah Virus (NiV) Threat: NiV is a severe public health risk due to its high mortality rate, broad host range, multiple transmission modes, and lack of effective treatment. Outbreaks have occurred frequently in South and Southeast Asia, particularly in Bangladesh and India, leading to high fatality rates. C_LIO_LICross-Border Concerns: NiVs ability to transmit between humans and domestic animals raises concerns about its potential to cross regional borders and cause pandemics. It has been recognized as a high-priority pathogen by the World Health Organization. C_LIO_LILack of Treatment: Currently, there are no approved specific antiviral treatments or vaccines for NiV. Patients receive supportive care and some drugs used for other viruses, despite their side effects. C_LIO_LITargeting NiV Glycoprotein G: The study focuses on NiV glycoprotein G (NiV-G) as a target for potential anti-Nipah drugs due to its crucial role in viral entry. This glycoprotein mediates viral attachment and entry into host cells. C_LIO_LIComputational Drug Discovery: The research employs computational methods, including virtual screening and molecular dynamics simulations, to identify potential inhibitors of NiV-G from a dataset of Peruvian phytochemicals, particularly procyanidins B2, B3, B7, and C1. These compounds showed promising binding affinities, stable interactions, and favorable binding energies with NiV-G, making them potential lead compounds for drug development. C_LI