Virtual Screening-Based Identification of Potent DENV-3 RdRp Protease Inhibitors via In-House Usnic Acid Derivative Database

Abstract

Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic disease and dengue shock syndrome (DSS), transmitted predominantly in tropical and subtropical regions by Aedes aegypti. It infects millions of people and causes thousands of deaths each year, but there is no antiviral drug against DENV. Usnic acid lately piqued the interest of researchers for extraordinary biological characteristics, including antiviral activity. Based on high larvicidal activities against Aedes aegypti, this study aims to search usnic acid derivatives as novel anti-DENV agents through a combination of ligand-based and pharmacophore-based virtual screening. One hundred and sixteen (116) usnic acid derivatives were obtained from a database of 428 in-house usnic acid derivatives through pharmacophore filtering steps. Subsequent docking simulation on DENV-3 NS-5 RdRp afforded 41 compounds with a strong binding affinity towards the enzyme. The pharmacokinetics and drug likeness prediction resulted in seven hit compounds, which eventually undergo cytochrome P450 enzyme screening to obtain the lead compound, labelled as 362. In addition, molecular dynamic (MD) simulation of lead compound 362 was performed to verify the stability of the docked complex and the binding posture acquired in docking experiments. Overall, the lead compounds have shown a high fit value of pharmacophore, strong binding affinity towards RdRp enzyme, good pharmacokinetics, and drug likeness properties. The discovery of a new usnic acid derivative as a novel anti-DENV agent targeting RdRp could lead to further drug development and optimization to treat dengue.

Pharmacophore-based Molecular Docking of Usnic Acid Derivatives to Discover Anti-viral drugs Against Influenza A Virus

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-Based Virtual Screening Towards The Discovery of Usnic Acid Derivatives as Novel mTOR Inhibitor to Treat Breast Cancer

“…The three-dimensional (3D) structure was created from 2D under the CHARMm force field with Discovery Studio Client 16.1. The ligand was prepared by using the CHARMm force field in Discovery Studio Client 16.1 by the generation of low-energy ring conformations and all compounds were by default set to a pH range of 5.0-9.0 for suitable protonation state (Roney et al, 2021).…”

“…All the hydrogen atoms, missing amino acid residues, and the looped segments around the active sites of protein were all inserted into the protein model. In addition, all the water molecules around the macromolecule were removed (Roney et al, 2021).…”

Evaluation of potential bacterial protease inhibitor properties of selected hydroxyquinoline derivatives: an in silico docking and molecular dynamics simulation approach

“…Molecular dynamics (MD) simulation studies are frequently used to verify the stability of leaddocked complexes and the binding posture acquired in docking experiments. MD simulations were performed using the Desmond (Schrödinger Maestro-Desmond Interoperability Tools) program for 100 nanoseconds (ns) time span (Roney et al, 2021). In this study, to assess such an effect, a number of parameters, including the RMSD, Root Mean Square Fluctuation (RMSF), and H-bond occupancy during simulation events of protein-ligand complexes, were explored rigorously.…”