Structure-Based Virtual Screening and Molecular Dynamics Simulation for Identifying Potential Therapeutics against Herpes Simplex Encephalitis

Essentially regarded as HSV-1 caused, Herpes Simplex Encephalitis is an acute and lethal form of neuroinfections with scarcely any options for treatment. Here, we have applied structure-based virtual screening and molecular dynamics (MD) simulations in an effort to find potential inhibitors targeting the viral thymidine kinase mutant Y101F (PDB ID: 1E2L), a crucial enzyme in the replication of HSV. A library of FDA-approved drugs was screened against the active site of 1E2L, and five drugs showing good binding affinity and beneficial interactions with important residues have been chosen: Dutasteride, Paritaprevir, Pimozide, Lumacaftor, and Tucatinib. Next, MD and Normal Mode Analysis (NMA) offered complementary mechanistic insights into the varying degrees of structural flexibility, conformational dynamics, and possible allosteric regulation of 1E2L . Shape and B-factor comparison highlighted flexible regions for the binding, while eigenvalue and variance analyses stressed the importance of low-frequency modes in the motion of molecules. Covariance mapping yielded correlated or anti-correlated movements within the residues integral to allosteric interactions, while the Elastic Network Model (ENM) was employed to reveal rigid and flexible regions that drive functional dynamics. Taken together, these findings point toward the selected compounds being reasonable candidates for repurposing as anti-HSV therapeutics via inhibition of the viral kinase. The combined method involving virtual screening and MD simulations is set up as a framework for rational drug development against HSE.