Volume 7(6): 367-373 (2015) - 367 J Microb Biochem Technol ISSN: 1948-5948 JMBT, an open access journal Sharma et al., J Microb Biochem Technol 2015, 7:6 DOI: 10.4172/1948-5948.1000240 Research Article Open Access Denovo Designing, Virtual Screening and Lead Optimization of Potential Drug Candidate for Herpes Disease Monica Sharma 1,2 *, Puneet Rawat 2 and Ankita Mehta 2 1 Department of Biotechnology, School of Biosciences and Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, India 2 Department of Biotechnology, Delhi Technological University, Main Bawana Road, Shahbad Daulatpur, Delhi, India *Corresponding authors: Monica Sharma, Department of Biotechnology, Delhi Technological University, Main Bawana Road, Shahbad Daulatpur, Delhi, India, Tel: +91-9717386785; E-mail: monashimla@gmail.com Received September 26, 2015; Accepted October 17, 2015; Published October 24, 2015 Citation: Sharma M, Rawat P, Mehta A (2015) Denovo Designing, Virtual Screening and Lead Optimization of Potential Drug Candidate for Herpes Disease. J Microb Biochem Technol 7: 367-373. doi:10.4172/1948-5948.1000240 Copyright: © 2015 Sharma M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: HSV; ICP-47; eLEA3D; Denovo designing; Bioisosteres Introduction Herpes simplex viruses (HSV) 1 and 2, the members of herpes virus family Herpesviridae are ubiquitous, highly contigious agents which infect humans [1,2]. Tey cause cold sores, herpetic keratitis and genital herpes [3-5]. An estimated 400 million people worldwide are currently infected by HSV-2 and infection of HSV-1 is spreading to developed regions like USA, Western Europe, Australia and New Zealand [WHO Fact Sheet, 2015]. HSV-1 persists in the body in dormant state by escaping the immune system and results in sporadic viral reactivation [6]. HSV evades the immune system by interfering with MHC Class I antigen presentation on the cell surface. Infected cell protein (ICP) 47 caused major histocompatibility complex (MHC) class I proteins retaintion in the endoplasmic reticulum (ER). MHC presents the antigen to CD + 8 T cells that are inhibited afer expression of ICP 47 in the cell [7]. ICP 47 blocks peptide (viral epitope) transport across the ER membrane by transporter associated with antigen processing (TAP) [8,9] so that MHC class I proteins remain in ER without peptides and cytotoxic T- lymphocytes activation can be stopped. Tis allows virus to reside for a protracted period in the host. Due to serious threat to human population a proper treatment and cure of HSV is required. For last two decades HSV glycoprotein D, has been the predominant HSV vaccine candidate [10,11], but the outcome of clinical trials of the vaccine have been really disappointing [12]. Antiviral drugs (valacyclovir, acyclovir, famciclovir, etc.) used against HSV infection, inhibit DNA polymerases and slows down infection by reducing viral replication but does not cure the infection completely [13]. Inappropriate prescribing and wide spread uncontrolled use of antiviral drugs led to emergence of resistance in the viruses. Recently, it has been observed that natural serine protease inhibitor (serpins) like serpinantithrombin III (AT III) inhibit HSV infection during an entry event. Antithrombin III demonstrated a promising result at experimental levels but yet it is far from any therapeutic use [13,14]. Due to inaccessibility of any efective drug and vaccine there is therefore, an urgent need for an efective HSV vaccine or drug that provides protection against infection and also thwart the virus entering a latent state [15]. Computer aided drug discovery design (CADD) has emerged as a way to signifcantly decrease compounds screening while retaining same level of lead compound discovery at the same time [16]. In the present manuscript we have designed lead compound by de- novo designing strategy and molecule having highest score was further optimized by virtual screening to increase its afnity to target and reduce toxicity by toxicological analysis by online ADMET profling tools of FAF DRUG 20 online tool and ORISIS data warrior. Methodology Sequence retrival DNA sequence of ICP-47 of HSV-2 was retrieved from NCBI and it was blasted to human genomic and transcriptomic database. Te structure of target protein ICP-47 was retrieved from rcsb.org in PDB (text) format (PDB I.D. 1QLO). Denovo drug designing Afer exhaustive literature survey and database searching, no ligand was found that bind to this target, so automated de-novo drug design strategy was adopted to get a hit molecule. eLEA3D program was used for denovo generation of ligand, which create new molecules by using a library of molecular fragments and by determining best combinations of molecular fragments that ft user-defned physicochemical properties Abstract Herpes simplex virus (HSV1, HSV 2) is a neurotropic and neuroinvasive virus which becomes latent and causes a lifelong infection. HSV-1 and 2 produce infected cell protein (ICP)-47 against MHC class I antigen presentation pathway by inhibiting the transporter associated with antigen processing (TAP). ICP 47 is also responsible for evasive nature of HSV in human immune system. Currently available antiviral drugs and vaccines only slowdowns the infection but it does not cure the infection. In present study, we have in silico designed a potential drug candidate against HSV ICP-47 target through de-novo pathway using eLEA3D. The derived ligand docked with the natural viral receptor ICP-47 showed the binding affnity of -4.07, but it was found toxic in FAF DRUG online ADMET tool, due to presence of high risk imine group. Further manual optimization led to generation of many bioisosteres and fnal lead structure showed no toxicity and a high binding affnity of -7.53. Our designed lead can act as a potential therapeutic compound against HSV. Journal of Microbial & Biochemical Technology J o u r n a l o f M i c r o b i a l & B i o c h e m i c a l T e c h n o l o g y ISSN: 1948-5948