All-Atom Perspective of the DENV‑3 Methyltransferase\nInhibition Mechanism

The Dengue virus (DENV) is an enveloped,\nsingle-stranded RNA virus\nwith several antigenically distinct serotypes (DENV-1 to DENV-5).\nDengue fever, as a major public health threat transmitted by mosquitoes,\naffects millions of people worldwide (especially in tropical and subtropical\nregions). Toward drug developments of DENV, the nonstructural protein\n5 methyltransferase (MTase) serves as an attractive target. The MTase\ntransforms <i>S</i>-adenosyl methionine to <i>S</i>-adenosyl homocysteine (SAH), which is thereby selected as the target\nwith which external drugs compete with. In this work, using alanine\nscanning with generalized Born and interaction entropy (ASGB-IE),\nwe provide an all-atom perspective of the protein–ligand interactions\nformed by DENV-3 MTase and SAH derivatives. Residues with consistently\nhigh contributions to stabilization are summarized, and the general\nDENV-3 MTase inhibition mechanism is elucidated. Additionally, the\nmutational impact on binding thermodynamics is found to be entropy-driven.\nWe also highlight the advantage of the ASGB-IE method for affinity\nestimation compared to standard end-point protocols, which is highly\nrelated to the selection of interfacial residues in free energy estimation.\nFinally, we performed a thorough scan of the mutational space on critical\nsites (saturation mutagenesis) and identified 14 mutants causing resistance\nto the current inhibitors.