الفهرس 
A Computational Study for Potential Antiviral Compounds against Nipah Virus
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Abstract
Nipah virus (NiV) is the deadliest zoonotic member in the Paramyxoviridae
family, with significant pandemic potential. Until now, no vaccines or therapeutic agents
are available to treat and control NiV infections. 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. The large (L) protein
of Mononegavirales performs transcription and genome replication. One of the important
domains in L is the RNA-dependent RNA polymerase (RdRp), a promising target for
antiviral drugs. Computational rigorous homology modeling was employed to predict the
secondary structure of the L protein of NiV. The molecular docking approach evaluated a
panel of nucleotide analogs previously reported to inhibit different RNA viruses. Best
binder compounds were subjected to molecular dynamics (MD) simulation for 100 ns to
validate their binding to the RdRp. Molecular Mechanics/Generalized-Born Surface Area
(MM/GBSA) calculations were performed to estimate the binding free energy. Similarly,
virtual screening was carried out to find lead small-molecule compounds disrupting
nucleoprotein-phosphoprotein interactions as a starting material for the discovery of new
antiviral drugs. The hotspot residues at the 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. Few
nucleoside analogs showed good binding affinities similar to the genuine ribonucleotide.
Galidesivir, AT-9010, and Norov-29 scored the top nucleotide analogs to bind to the RdRp.
Their binding affinities estimated by molecular docking ranged from – 8.2 to − 8.4
kcal/mol. However, binding free energies are obtained by MM/GBSA (− 31.01 ± 3.9 to
−38.37 ± 4.8 kcal/mol). Likewise, molecular docking identified ten potential inhibitors of
N
0P interaction with a range of binding affinities from – 9.66 kcal/mol to – 11.29 kcal/mol. Subsequent MD simulations and free energy calculations by MM/GBSA identified
apogossypol derivatives as potential leads of N0P inhibitors. MM/GBSA calculations
estimated the binding free energies to range from − 23.61 ± 4.05 to − 48.63 ± 6.49 kcal/mol.
Pharmacokinetic and medicinal chemistry properties of top hits were also predicted. These
findings are expected to provide new insights for efficient modifications and optimization
of a new class of antiviral drugs. Purine nucleotide analogs are expected to harbor the
scaffold for an effective drug against NiV. Finally, this study is expected to provide a
starting point for medicinal chemistry and drug discovery campaigns toward identifying
effective chemotherapeutic agent(s) against NiV.