Molecular dynamic approach in the regulation of systemic XCT antiporter through biologically active molecules for ischemic stroke

Abstract

ABSTRACT The heterodimeric amino acid transporter systemic XCT plays a crucial role in redox balance regulation by facilitating L-cystine and L-glutamate import/export in a 1:1 ratio. Translating findings from preclinical to clinical contexts poses challenges due to interspecies receptor variations. To understand these differences and achieve success during translating studies, in silico analysis of FDA-approved drugs was performed against three species for systemic XCT receptors with UniProt-ids D4ADU2 (Rattus norvegicus), Q9WTR6 (Mus musculus), and Q9UPY5 (Homo sapiens). Homology modelling produced validated 3D structures for D4ADU2 and Q9WTR6, achieving an excellent model quality score (∼84%). Virtual screening identified common hits in Rat and Mouse Homology Modelled Structures (RHMS and MHMS), including Avodart, Rolapitant, and Olmesartan. In Homo sapiens (PDBs 7P9U and 7P9 V), common hits Dihydroergotamine and Ergotamine showed binding affinities of −12.3 to −10.1 kcal/mol as compared to glutamate and cystine (−4.9 to −5.9 kcal/mol) within the same binding pocket. A 500 ns MD simulation confirmed structural stability, positive correlations and limited atomic displacements. Free energy calculations highlighted the top compounds highly favourable binding affinities across all receptors. These results shed light on structural and dynamical variations among the interspecies receptors-ligands interactions which provide valuable insights into transitioning from preclinical to clinical settings.