Identification of NS2B-NS3 Protease Inhibitors for Therapeutic Application in ZIKV Infection: A Pharmacophore-Based High-Throughput Virtual Screening and MD Simulations Approaches

Abstract

Zika virus (ZIKV) pandemic and its implication in congenital malformations and severe neurological disorders had created serious threats to global health. ZIKV is a mosquito-borne flavivirus which spread rapidly and infect a large number of people in a shorter time-span. Due to the lack of effective therapeutics, this had become paramount urgency to discover effective drug molecules to encounter the viral infection. Various anti-ZIKV drug discovery efforts during the past several years had been unsuccessful to develop an effective cure. The NS2B-NS3 protein was reported as an attractive therapeutic target for inhibiting viral proliferation, due to its central role in viral replication and maturation of non-structural viral proteins. Therefore, the current in silico drug exploration aimed to identify the novel inhibitors of Zika NS2B-NS3 protease by implementing an e-pharmacophore-based high-throughput virtual screening. A 3D e-pharmacophore model was generated based on the five-featured (ADPRR) pharmacophore hypothesis. Subsequently, the predicted model is further subjected to the high-throughput virtual screening to reveal top hit molecules from the various small molecule databases. Initial hits were examined in terms of binding free energies and ADME properties to identify the candidate hit exhibiting a favourable pharmacokinetic profile. Eventually, molecular dynamic (MD) simulations studies were conducted to evaluate the binding stability of the hit molecule inside the receptor cavity. The findings of the in silico analysis manifested affirmative evidence for three hit molecules with −64.28, −55.15 and −50.16 kcal/mol binding free energies, as potent inhibitors of Zika NS2B-NS3 protease. Hence, these molecules holds the promising potential to serve as a prospective candidates to design effective drugs against ZIKV and related viral infections.

ZIKV Inhibitors Based on Pyrazolo[3,4-d]pyridazine-7-one Core: Rational Design, In Vitro Evaluation, and Theoretical Studies

“…The benzimidazole ring of the cocrystallization ligand was sandwiched between the side chains of Ala132-Tyr161, so both of these amino acids were considered key residues. 45 The docking protocol showed that both compounds interact with the key amino acids at the active site of NS2B-NS3 protease with binding energies lower than −7.6 kcal/mol. The 9b -NS2B-NS3 complex formed a catalytic triad at the active site characterized by the presence of the His51, Asp75, and Ser135 residues, resulting in a closed conformation of the oxyanion orifice.…”

“…The inhibitors’ binding mode with protease was previously reported, and His51, Asp75, and Ser135 were key amino acids that participated in H-bond and hydrophobic interactions. , Especially, Ser135 played a vital role in the inhibition activity of the compound with this target enzyme. The benzimidazole ring of the cocrystallization ligand was sandwiched between the side chains of Ala132-Tyr161, so both of these amino acids were considered key residues . The docking protocol showed that both compounds interact with the key amino acids at the active site of NS2B-NS3 protease with binding energies lower than −7.6 kcal/mol.…”

Revealing mechanism of Methazolamide for treatment of ankylosing spondylitis based on network pharmacology and GSEA

“…Molecular dynamics simulations have become a standard tool for the investigation of biomolecules to assess stability and flexibility. Simulations are performed of ever bigger systems using more realistic boundary conditions and better sampling due to longer sampling times to ensure the reliability of molecular docking 87 – 89 . In this study, re-docking and molecular dynamics simulations were completed to ensure the reliability of molecular docking.…”

The natural breakthrough: phytochemicals as potent therapeutic agents against spinocerebellar ataxia type 3

“…Autodock Vina, the open-source software for docking analysis of the selected best-screen active compounds, was used 21 , 22 . The pdbqt files for the protein and ligands were created utilizing MGL tools.…”