In silico investigation of acyclovir derivatives potency against herpes simplex virus

Abstract

Herpes simplex virus (HSV) is a major human pathogen, sub-divided into two types: HSV-1 which causes oral and perioral infections and HSV-2 which causes genital herpes. The global disease burden is high with 67% and 11% of the World's population being infected with HSV-1 and HSV-2 respectively. Acyclovir, an FDA approved drug, is a synthetic purine nucleoside analogue used for the treatment of HSV infections. The drug acts via the viral encoded thymidine kinase and competitively inhibits viral DNA polymerase. Emerging HSV resistance to acyclovir and lack of approved vaccines necessitates need for effective strategies to circumvent the viral infection. Derivatives of acyclovir were modelled using computer aided drug design techniques through Chemsketch and drugability determined based on Lipinski's Ro5 where a Python filtering code was created and derivatives with zero non-violations were selected. Putative biological targets were determined through network pharmacology and validated through gene ontology. Molecular docking with known and putative targets was done to determine the binding affinities of the acyclovir derivatives. Based on enzyme inhibition scores, pharmacokinetics prediction was done on Molinspiration while pharmacodynamics predictions were done on AdmetSAR based on bioavailability scores. Thirty acyclovir derivatives were modelled of which 22 had zero non-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. The molecule was further optimized generating (2‐[(6‐methyl‐6,9‐dihydro‐3H‐purin‐9‐yl)methoxy]ethan‐1‐ol which had a better bioavailability and a higher blood brain barrier value of 0.9880 indicating possible better patient tolerance. 2‐[(6‐methyl‐6,9‐dihydro‐3H‐purin‐9‐yl)methoxy]ethan‐1‐ol had an enzyme inhibition score of 0.90 and binding energies of -5.1 kcal/mol when docked against thymidine kinase. The intra-viral HSV PPI network was analysed and DNA replication helicase (UL5) and serine /threonine-protein kinase (US3) were selected due to functional similarity with thymidine kinase with kappa statistics value of 0.30 and 0.24 respectively. Gene enrichment analysis indicated that the biological targets UL5 and US3 had a significant P value of 0.62 based on Benjamin Correction at P<0.05. The study recommends in vitro and in vivo validation of this novel compound and molecular validation of the two new potential biological targets for possible development of new anti-herpes therapeutic compounds.