Homology Modeling of DNA polymerases of Herpesviridae family and structure-based virtual screening for inhibitor identification.

Subhashini Pandey,Som Dutt,N Srivastava,Jitender Kumar

doi:10.7324/japs.2015.501208

Abstract

Human herpes viruses are responsible for the several transmitted infections in human. It is known that the DNA polymerase enzyme is one of the putative targets for herpes. Therefore, it is of interest to model all known DNA polymerases of herpesviridae family. So, all the DNA polymerases of herpesviridae without any crystal structure were modeled using HHV-1 DNA polymerase as a template. Modeled structures were screened by ramachandran plots and Discrete Optimization of Protein Energy (DOPE) scores. To find out multi-target inhibitor for herpesviridae, 21 natural antiviral compounds were selected from literature and screened using Lipinski’s rule of five. Binding pose of acyclovir with HHV-1 DNA polymerase was taken for the comparative docking study. Comparative binding analysis was done after settling of 120 and eight partial mono flexible protein-ligand docking sets for natural compounds and acyclovir, respectively. From the study it is found that alliin and gallic acid exhibit good binding affinity than acyclovir and other natural compounds. So here we purpose these two compounds which can be potential candidates to inhibit herpesviridae family.

Highlights

Herpes viruses are the leading cause of several transmitted infections in humans that are chronic, widespread and infectious during both its symptomatic and asymptomatic periods and are second only to influenza and cold viruses (Bernardino et al, 2008; Smith and Kennell, 1981). Infections caused by this family of viruses are endemic and sexual contact is a significant mode of transmission for herpes simplex virus 1 and 2 (HSV-1, HSV-2), human cytomegalovirus (HHV-5) and likely Karposi's sarcoma herpesvirus (HHV-8) (Anderson et al, 2014; Collins and Medveczky, 2002)
Binding mode of acyclovir and human herpesvirus (HHV)-1 DNA polymerase has already been reported that explains acyclovir interacts with highly conserved KKKY motif present in the binding cleft to block the replication of viral DNA
Studies state that the resistance to nucleoside inhibitors is a result of mutations in highly conserved region YGDTDS of HHV-1 DNA polymerase

Summary

INTRODUCTION

Herpes viruses are the leading cause of several transmitted infections in humans that are chronic, widespread and infectious during both its symptomatic and asymptomatic periods and are second only to influenza and cold viruses (Bernardino et al, 2008; Smith and Kennell, 1981). The parameters used for the screening of the structure models were DOPE score and ramachandran (RC)plot analysis. Fifteen screened compounds were further docked at the active site of the DNA polymerases of Herpesviridae family family. From the set of screened 15 compounds, alliin and gallic acid showed good binding affinity than the control acyclovir These findings may provide useful insights for designing new potent multi-target inhibitors to fight against the infections of Herpesviridae family. Screening of ten generated models for each target was done with DOPE score and RC plot analysis. Ligand Selection In order to find the potent ligand molecules for Herpesviridae family, a set of 21 natural compounds (known antiviral activity), was taken from the literature. Visualization of the docked structure was performed on PyMol molecular graphics program, a comprehensive software package for rendering and animating 3Dstructures (Lilland Danielson, 2011)

RESULTS AND DISCUSSIONS

H Acceptors 0 3 0 0 4 6 6 5 2 1 0 0 1 1 1 1 1 5

CONCLUSION