Discovery of novel inhibitors from medicinal plants for v-domain ig suppressor of t-cell activation

Muneer, Iqra and Ahmad, Sajjad and Naz, Anam and Abbasi, Sumra Wajid and Alblihy, Adel and Aloliqi, Abdulaziz A. and Aba Alkhayl, Faris F. and Alrumaihi, Faris and Ahmad, Sarfraz and El Bakri, Youness and Tahir Ul Qamar, Muhammad (2021) Discovery of novel inhibitors from medicinal plants for v-domain ig suppressor of t-cell activation. Frontiers In Molecular Biosciences, 8. ISSN 2296-889X, DOI

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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 angstrom. 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.

Item Type: Article
Uncontrolled Keywords: VISTA; breast cancer; medicinal plant; phytochemical; MD simulation
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms Zaharah Ramly
Date Deposited: 01 Jun 2022 07:25
Last Modified: 01 Jun 2022 07:25

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