Abstract:
Herpes simplex virus (HSV) is a prevalent human pathogen with 67% and 13% of the world’s population infected with HSV type-1 (HSV-1) and HSV type-2 (HSV-2), respectively. HSV-1 causes oral and perioral infections while, HSV-2 causes genital herpes. Acyclovir, a purine nucleoside analogue, is used for treatment of HSV-1 and HSV-2 infections. The mechanism of action of acyclovir is monophosphorylation by viral thymidine kinase (TK). The emerging HSV resistance to acyclovir due to mutation on viral TK and DNA polymerase necessitates an urgent need for effective strategies to circumvent HSV. This study investigated the potency of acyclovir derivatives against HSV through in silico approaches. Ligand-based drug design was used to model acyclovir derivatives on Chemsketch version 2018.2.5. Drugability was determined based on Lipinski’s Rule of Five. Putative targets were identified through network pharmacology and validated through gene ontology (GO). Molecular docking was used to determine the binding affinities using Autodock Vina. The pharmacokinetic prediction was done using enzyme inhibition scores on Molinspiration. Pharmacodynamic predictions were based on bioavailability scores on AdmetSAR 2.0. The scores for permeability (Caco2), Blood Brain Barrier (BBB), Human Intestinal Absorption (HIA) and P- glycoprotein inhibitor were generated. The resazurin assay was used to test cytotoxicity. Twenty two acyclovir derivatives had zero violations. 2-[(3, 6-dihydro-9H-purin-9-yl)methoxy]ethan-1-ol) had the highest enzyme inhibition score at 1.0 compared to 0.84 for acyclovir. This molecule was optimized to (2‐[(6‐methyl‐6,9‐dihydro‐3H‐purin‐9‐yl)methoxy]ethan‐1‐ol, which had a better bioavailability and a higher BBB value of 0.9880 indicating tolerance. DNA replication helicase (UL5) and serine /threonine-protein kinase (US3) were selected based on functional similarity with TK, kappa values were 0.30 and 0.24, respectively. The IC50 of acyclovir at 24 hours and 48 hours were 16.18μg/ml and 38.10μg/ml with R squared values of 0.7894 and 0.9098, respectively. The optimized lead compound, together with its putative targets provides a mechanism to circumvent HSV drug resistance associated with the use of acyclovir. The study recommends in vitro and in vivo efficacy and toxicity studies for possible development of anti-herpes drug compounds.
