Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation

Abstract

V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than −6 kcal/mol were found to have two common hydrogen bond interactions with VISTA active site residues: Arg54 and Arg127. The dynamics of the compound–VISTA complexes were further explored to infer binding stability of the systems. Results revealed that the compound 14187087 and 6494266 systems are highly stable with an average RMSD of 1.31 Å. Further affirmation on the results was achieved by running MM-GBSA on the MD simulation trajectories, which re-ranked 14187087 as the top-binder with a net binding energy value of −33.33 kcal/mol. In conclusion, the present study successfully predicted natural compounds that have the potential to block the function of VISTA and therefore can be utilized further in experimental studies to validate their real anti-VISTA activity.

Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence

“…This treatment strategy is considered a game changer in cancer therapy and involves molecules that can negatively alter the immune response. Immune checkpoints can be readily blocked by antibodies or modified by recombinant ligands ( Pardoll, 2012 ; Muneer et al, 2021 ). Immune checkpoint inhibitory antibodies aid in the attachment of molecules capable of stopping the immune response to tumor-infiltrating lymphocytes, leading to reactivation of antitumor immune responses ( Singh et al, 2021 ).…”

“…In most cases, emergence occurs from the milk duct, while other minor cases occur from lobules. The cancer of the ductile region is known as ductal carcinoma, while those involving mammary lobules are called lobular carcinomas ( Medina et al, 2020 ; Muneer et al, 2021 ). According to the World Health Organization (WHO) reports, breast cancer is placed second on the list of common diseases worldwide.…”

Insights into the Binding of Receptor-Binding Domain (RBD) of SARS-CoV-2 Wild Type and B.1.620 Variant with hACE2 Using Molecular Docking and Simulation Approaches

“…For each complex, the electrostatic, van der Waal, and total binding energies were calculated with the MM/GBSA method [ 48 ]. These methods are widely used and have been shown to be quite accurate [ 49 , 50 , 51 , 52 , 53 ]. Each aforementioned energy term was calculated as part of the total binding free energy.…”

Targeting the RBD of Omicron Variant (B.1.1.529) with Medicinal Phytocompounds to Abrogate the Binding of Spike Glycoprotein with the hACE2 Using Computational Molecular Search and Simulation Approach

“…Post-Simulation Validation of the Top Hits 2.5.1. The Binding Free Energy Calculations For the estimation of the binding free energies of various biological complexes such as protein-DNA/RNA or protein-protein, the MMGBSA is the most authentic approach used in different research investigations [34][35][36][37][38]. In the present study, the script MMPBSA.py was used to calculate the binding free energy of the protein-ligand complexes by considering 2500 snapshots.…”