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image of Identifying Novel Inhibitors for Dengue NS2B-NS3 Protease by Combining Topological similarity, Molecular Dynamics, MMGBSA and SiteMap Analysis

Abstract

Introduction

DENV NS2B-NS3 protease inhibitors were designed based upon the reference molecule, 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl) benzenesulfonamide, reported by our team with the aim to optimize lead compound rational approach. Top five best scoring molecules with zinc ids ZINC23504872, ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613 bearing ‘pyrimidin-4(3H)-one’ basic scaffold have been identified as a promising candidate against DENV protease enzyme.

Methods

The shape and electrostatic complementary between identified HITs and reference molecules were found to be Tanimotoshape 0.453, 0.690, 0.680, 0.685 & 0.672 respectively and Tanimotoelectrostatic 0.211, 0.211, 0.441, 0.442, 0.442 and 0.442 respectively. The molecular docking studies suggested that the identified HITs displayed the good interactions with active site residues and lower binding energies. The stability of docked complexes was assessed by MD simulations studies. The RMSD values of protein backbone (1.6779, 3.1563, 3.3634, 3.3893 & 3.0960 Å) and protein backbone RMSF values (1.0126, 1.0834, 1.0890, 0.9974 & 1.0080 Å respectively) for all top five HITs were stable and molecules did not fluctuate from the active pocket during entire 100ns MD run.

Results

The druggability Dscore below 1 indicate the tightly binding of ligand at the active site. Dscore for ZINC23504872 was found to be 1.084 while for the second class of compounds ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613, 0.503, 0.484, 0.487 and 0.501 Dscores were observed. In-silico ADMET calculations suggested that all five HITs were possessed the drug likeliness properties and did not violate the Lipinski’s rule of five.

Conclusion

Summing up, these in-silico generated data suggested that the identified molecules bearing pyrimidin-4(3H)-one would be promising scaffold for DENV protease inhibitors. However, experimental results are needed to prove the obtained results.

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2024-10-29
2025-04-10

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Identifying Novel Inhibitors for Dengue NS2B-NS3 Protease by Combining Topological similarity, Molecular Dynamics, MMGBSA and SiteMap Analysis
Bentham Science Publishers ; https://doi.org/10.2174/0115734099329789240905141013
/content/journals/cad/10.2174/0115734099329789240905141013
/content/journals/cad/10.2174/0115734099329789240905141013
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  • Article Type:     Research Article
Keywords: MMGB/SA ; Dengue ; MD Simulation studies ; shape and electrostatic screening ; DENVNS2B-NS3 Pro ; molecular modelling

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