Main Article Content
Background: Nipah virus (NiV) is the deadliest zoonotic member in the Paramyxoviridae family with a significant pandemic potential. Until now, no vaccines or therapeutic agents are available to treat and control NiV infections. As in all paramyxoviruses, Phosphoprotein is a pivotal cofactor for viral genome replication and genome encapsidation through multiple interactions with the RNA polymerase and the nucleoprotein.
Aim: This study was conducted to find lead small-molecule compounds disrupting nucleoprotein-phosphoprotein interaction as a starting material for the discovery of new antiviral drugs.
Methodology: In this work, the hotspot residues at nucleoprotein-phosphoprotein interface were identified via energy decomposition analysis followed by a structure-based molecular docking of protein-protein interaction inhibitors from the iPPI-DB database. Moleular dynamics simulations and Molecular Mechanics/Generalized-Born Surface Area (MM/GBSA) claculations were also performed for the best candidate hits. Pharmacokinetic and medicinal chemistry properties of top hits were also predicted.
Results: Molecular docking identified ten potential inhibitors with a range of binding affinities from – 9.66 to – 11.29 kcal/mol. Subsequent molecular dynamics simulations and free energy calculations by Molecular Mechanics/Generalized-Born Surface Area (MM/GBSA) identified apogossypol derivatives as potential leads. MM/GBSA calculations estimated the binding free energies to range from − 23.61 ± 4.05 to − 48.63 ± 6.49 kcal/mol.
Conclusion: The identified hits are believed to be good starting material for further structural improvement. The findings are also expected to provide new insights for efficient modifications and optimization of such compounds as a new class of antiviral drugs.