AUTHOR=Muneer Iqra , Ahmad Sajjad , Naz Anam , Abbasi Sumra Wajid , Alblihy Adel , Aloliqi Abdulaziz A. , Aba Alkhayl Faris F. , Alrumaihi Faris , Ahmad Sarfraz , El Bakri Youness , Tahir Ul Qamar Muhammad TITLE=Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation JOURNAL=Frontiers in Molecular Biosciences VOLUME=8 YEAR=2021 URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.716735 DOI=10.3389/fmolb.2021.716735 ISSN=2296-889X 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.