Repurposing of approved drugs and nutraceuticals to identify potential inhibitors of SARS-COV-2’s entry into human host cells: a structural analysis using induced-fit docking, MMGBSA and molecular dynamics simulation approach

Drug-induced liver injury can be caused by any drugs, their metabolites, or natural products due to the inefficient functioning of drug-metabolizing enzymes, resulting in reactive oxygen species generation and leading to oxidative stress-induced cell death. For protection against oxidative stress, our cell has various defense mechanisms. One of the mechanisms is NRF2 pathway, when activated, protects the cell against oxidative stress. Natural antioxidants such as Sesamol have reported pharmacological activity (hepatoprotective & cardioprotective) and signaling pathways (NRF2 & CREM) altering potential. A Computational analysis was done using molecular docking, IFD, ADMET, MM-GBSA, and Molecular dynamic simulation of the Schrödinger suite. A total of 63,345 Sesamol derivatives were downloaded for the PubChem database. The protein structure of KEAP1-NRF2 (PDB: 4L7D) was downloaded from the RCSB protein database. The molecular docking technique was used to screen compounds that can form an interaction similar to the co-crystalized ligand (1VX). Based on MM-GBSA, docking score, and interactions, ten compounds were selected for ADMET profiling and IFD. After IFD, five compounds (66867225, 46148111, 12444939, 123892179, & 94817569) were selected for molecular dynamics simulation (MDS). Protein–ligand complex stability was assessed during MDS. The selected compounds (66867225, 46148111, 12444939, 123892179, & 94817569) complex with KEAP1 protein shows good stability and bond retentions. In our study, we observed that the selected compounds show good interaction, PCA, Rg, binding free energy, and ADMET profile. We can conclude that the selected compounds can act as NRF2 activators, which should be validated using proper in-vivo/in-vitro models. Graphical abstract

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Virtual structure-based docking and molecular dynamics of FDA-approved drugs for the identification of potential IKKB inhibitors possessing dopaminergic activity in Alzheimer’s disease

Gurram

Satarker

Nassar

et al. 2022

Chem. Pap.

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In Alzheimer's disease (AD), neuroinflammation is detrimental in causing neurodegeneration. In the central nervous system, inhibitor of nuclear factor kappa B kinase subunit beta (IKK2/IKKβ/IKKB/IKBKB) signaling is linked to neuroinflammation-mediated learning and memory deficits through canonical pathway, while dopamine agonists have been known to reverse such effects. Our in silico analysis predicted if dopaminergic agonists could have IKKB inhibitory actions, to ameliorate neuroinflammation-associated learning and memory deficits. Here, the FDA-approved Zinc 15 database was screened with IKKB (PDB ID 4KIK). Potential molecules with IKKB inhibition were identified through docking, which also possessed dopaminergic activity. Molecular mechanics—generalized Born and surface area (MMGBSA), induced fit docking (IFD) and molecular dynamic (MD) studies of 100 ns simulation time were done. Apomorphine and rotigotine showed greater non-bonding and bonding interactions with amino acids of IKKB as compared to Aripiprazole in docking studies. The IFD studies predicted improved interactions with IKKB. MMGBSA scores indicated that the complex binding free energies were favorable, and MD studies showed an acceptable root mean square deviation between protein and ligands. The protein–ligand interactions showed hydrogen bonds, water and salt bridges necessary for IKKB inhibition, as well as solvent system stability. On the protein–ligand contact map, the varying color band intensities represented the ligand’s ability to bind with amino acids. Dopamine agonists apomorphine, rotigotine, and aripiprazole were predicted to bind and inhibit IKKB in in silico system. Graphical Abstract

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Repurposing of approved drugs and nutraceuticals to identify potential inhibitors of SARS-COV-2’s entry into human host cells: a structural analysis using induced-fit docking, MMGBSA and molecular dynamics simulation approach

Cited by 3 publications

References 59 publications

Molecular insights into Mmpl3 lead to the development of novel indole-2-carboxamides as antitubercular agents

Molecular insights into Mmpl3 lead to the development of novel indole-2-carboxamides as antitubercular agents

A computational study to identify Sesamol derivatives as NRF2 activator for protection against drug-induced liver injury (DILI)

Virtual structure-based docking and molecular dynamics of FDA-approved drugs for the identification of potential IKKB inhibitors possessing dopaminergic activity in Alzheimer’s disease

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