Targeting Human Bocavirus VP-2 Protein by Combining Pharmacophore, Molecular Docking and ADME-Tox Approaches to Identify Best-Optimized Novel Drug Candidate

Author Name(s): Abhay bankar, * Nishant kumar Soni, Rajnish Vashishtha, Neetu Verma, Manoj Jha, Chandan kumar Verma
Author Email: soninishant1990@gmail.com

Abstract

Human bocavirus (HBoV) belongs to a parvoviridae family. It has a single-stranded DNA etiologic agent and is known to cause lower respiratory tract infections in small and young children all over the world. Currently, there is no treatment or vaccination. The aim of the study was to describe the Human bocavirus VP 2 protein structure and discover the possible drug candidates that can be further used as possible drugs for dealing with infections caused by Human bocavirus.  Molecular docking was performed using AutoDock. The molecule presenting the finest binding energies (Ribavirin -7.72, Amantadine -6.64, and Anabasine -6.61) were finally selected as good drug candidates. These possible drug candidates were further used to produce a pharmacophore model for antiviral ligands using LigandScout. Later the pharmacophore based virtual screening was done against the pre-selected ligand library from zinc database, as a result the finest hits or leads for pharmacophore molecules were obtained. These hits or leads are used as ligands and subjected to molecular docking. The finest molecule was found to be ZINC41029220 -8.42 (Binding Energy), after obtaining the best hits ADME-Tox analysis performed. These molecules were used as inhibitors for Human bocavirus VP 2 protein.

Keyword

Human Bocavirus VP2 protein, molecular docking, pharmacophore, LigandScout, SiteHound-web, antivirals, binding energies, ADME-Tox analysis

Introduction

Human bocavirus 1 is from the family parvoviridae and genus bocavirus. This virus is related to severe acute respiratory infection. Noticed largely in respiratory secretions of the offspring with lower respiratory tract infections. It is spotted through the PCR amplification of sample form the upper respiratory tract. Human bocavirus affects the human respiratory tract and it replicates in the epithelial cells [1]. The pathophysiology of human bocavirus remains unidentified owing to doubt. It was found that virus protein 2 (VP2) displayed chief immunoreactivity. Consequently have taken into thought to learn the organization of VP2 protein. Protein interaction depends on the very complex intermolecular interaction with different types of ligands, proteins or other surfaces[2]. In receptor, there are certain favorable sites (known as pocket) having high binding affinity with the lignad known as pocket. [3]. The binding energies of the molecules utilized to recognize interactions amongst the target and the ligand molecule. To find the interaction between receptor and ligand, AutoDock tool [4] was used. It is widely non-commercial software that is mostly used for molecular docking as well as virtual screening [5]. The binding energies were found using pharmacophore [6]. Pharmacophore is a significant tool in drug discovery [7].  It is defined by ehrlich in year 1909  as a molecular conformation that carries (phoros) the vital aspect liable for drug (pharmacon) biological activity. Antiviral drugs are used in handling of viral infections [8].  There are about 15 antivirals used in this studies some of the antivirals used were

Acyclovir: Acyclovir sodium is crystal-like white powder having molecular formula C8H10N5NaO3 and M.W-247.19. It is used in dealing of infections formed by herpes simplex (HSV-1 as well as HSV-2) virus, herpes zoster (shingles) and varicella (chickenpox) [9]. Acyclovir used to study effect on canine parvovirus (CPV2) infection in the puppies. It was effective in stopping of CPV2 replication in puppies.

Rimantadine: Rimantadine is from amantadine class of drugs, which have antiviral properties against influenza A viruses. It prevents viral replication and inhibits ion channel membrane protein. They are not effective against influenza B viruses [10]. Rimantadine used in the treatment and prophylaxis of influenza A strains other than H5N1

 Ribavirin: For hepatitis C virus ribavirin is a nucleoside purine analog that is used in treatment but incompletely understood. Ribavirin is very important for hepatitis C therapy. It is used in presence of interferon ribavirin reduces relapse rates and improves sustained virological responses [11].

Amantadine: Amantadine is antiviral, inhibits influenza virus replication and is important treatment of human Parkinson’s disease. The recent studies have been made on amantadine to study its clinical applications, in numerous dissimilar virus infections e.g. herpes, herpes zoster neuralgia and form neuroleptic extrapyramidal movement disease to depression and cocaine dependence [12].

Anabasine: Anabasine hydrochloride is also a strong as well as important nicotinic acetylcholine receptor agonist. The chemical name of Anabasine is 3-Piperidin-2-ylpyridine hydrochloride with M.W-198.73. Its molecular formula is C10H14N2.HCl. It starts cholinergic nicotinic and muscarinic receptors and stimulates Ca-dependent catecholamine release from rat adrenomedullary cells. Anabasine has trans-3-hydroxynicotinine, 5-hydroxycotinine, and cotinine-N-oxide. Norcotinine, anabasine, and nicotine are compounds with structural resemblance and may yield mutual product ions Nicotine as well as anabasine have common ion change while trans-3-hydroxycotinine and cotinine-N-oxide have a mutual ion transition [13].

Conclusion

Till date there is no potential drug available that can cure the infections caused due to bocavirus 1.In the current work  researchers have targeted the VP2 protein by combining pharmacophore, molecular docking and ADME-Tox approaches. The antiviral molecule is  docked with the receptor. Top three molecules (Ribavirin- -7.72, Amantadine- -6.64, and Anabasine- 6.61) were used for pharmacophore modelling. A Total of 9 lacs molecules were screened through pharmacophore models which were obtained from top 3 antiviral molecules. Once running through pharmacophore model 3963 molecules were obtained. These molecules were also docked with main receptor vp2 protein and top 3 results were selected and those molecules were used.  1. ZINC41029220 – -8.46, 2. ZINC12385960 – -7.90, 3. ZINC00041375- -7.87. The modelled pharmacophores were proved to be more promising than the antiviral compounds themselves. The combination of these can used in clinical trials for developing a novel drug for Human bocavirus.

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