Binding Modes of Xanthine‐Derived Selective Allosteric Site Inhibitors of MTHFD2

Computational modeling of xanthine-based inhibitors binding to the allosteric site of MTHFD2, with promising anticancer activity, was carried out. Using docking/IFD, MD simulations and binding free energy calculations, the binding modes in the MTHFD2 and MTHFD1 allosteric sites were analyzed, establishing a clear correlation with biological activity and selectivity. MD trajectories were furthermore analyzed to verify reported conformational changes in MTHFD2.

Abstract

Methylenetetrahydrofolate dehydrogenase (MTHFD2) is a mitochondrial enzyme involved in 1 C metabolism that is upregulated in various cancer cells, but absent in normal proliferating cells. Xanthine derivatives are the first selective inhibitors of MTHFD2 which bind to its allosteric site. Xanthine derivatives (including the co-crystallized inhibitors) were herein interrogated by molecular/induced-fit docking, MM-GBSA binding free energy calculations and molecular dynamics simulations in both MTHFD2 and MTHFD1 (a close homolog expressed in healthy cells). The gained insights from our in silico protocol allowed us to study binding mode, key protein-ligand interactions and dynamic movement of the allosteric inhibitors, correlating with their experimental binding affinities, biological activities and selectivity for MTHFD2. The reported conformational changes with MTHFD2 upon binding of xanthine derivatives were furthermore evaluated and confirmed by RMSF analyses of the MD simulation trajectories. The results reported herein are expected to benefit in the rational design of selective MTHFD2 allosteric inhibitors.

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