Vol 10, Issue 5, 2017 Online - 2455-3891 Print - 0974-2441 ZIKA VIRUS SERINE PROTEASE COMPLEX (NS2B-NS3) INHIBITION BY 2-AMINO-5- {[(1Z) -AMINO ({[(Z) -BENZOYL] IMINO}) METHYL] AMINO} -N-(5-AMINO-7-{[CARBAMOYL (PHENYL) METHYL] AMINO} -6-OXOHEPTYL) PENTANAMIDE, IN SILICO STUDIES KALPANA VIRENDRA SINGH 1 *, RAMCHANDER MERUGU 2 , JEEVEN SINGH SOLANKI 1 1 Department of Chemistry and Pharmaceutical Chemistry, Madhav Science P.G. College, Ujjain, Madhya Pradesh, India. 2 Department of Biochemistry, Mahatma Gandhi University, Nalgonda, Telangana, India. Email: singhkalpana297@gmail.com Received: 25 January 2016, Revised and Accepted: 16 February 2017 ABSTRACT Objective: The present in silico study is taken to report 2-amino-5-{[(1Z) -amino ({[(Z) -benzoyl] imino}) methyl] amino} -N-(5-amino-7-{[carbamoyl (phenyl) methyl] amino} -6-oxoheptyl) pentanamide as Zika virus (ZIKV) NS2B-NS3 protease inhibitor. Methods: In silico studies performed on online docking servers. NS2B-NS3 serine protease from ZIKV with PDB ID: 5GJ4 a hydrolase with total structure weight of 102878.54 is selected as the target. Docking server is used for carrying out docking calculations. Lamarckian genetic algorithm and the Solis and Wets local search methods are used for performing docking simulations. Free energy calculations, hydrogen bond (HB) formation, polar and hydrophobic interactions and HB plot are studied in this study. Results: Binding pocket is found on a serine protease NS2B chain A. Binding site predictions propose NKK as the suitable ligand for binding, which has structure closely related to the proposed ligand2-amino-5-{[(1Z) -amino ({[(Z) -benzoyl] imino}) methyl] amino} -N-(5-amino-7-{[carbamoyl (phenyl) methyl] amino} -6-oxoheptyl) pentanamide. Free energy of binding is - 4.08 kcal/Mol and inhibition constant (Ki) is very less 1.02 mm. The ligand binds to chain A of NS2B and chain B of NS3 serine protease. The legend is bound to serine protease complex through strong HB, formed between THR 60 (A) and N6 of ligand, GLU62 (A) and N8 of ligand, ARG 55 (A) and N3 of ligand and ASN108 (B) and N7 of ligand apart from polar and hydrophobic interactions. Conclusion: Docking studies performed establishes the proposed ligand2-amino-5-{[(1Z)-amino ({[(Z)-benzoyl] imino}) methyl] amino} -N-(5- amino-7-{[carbamoyl (phenyl) methyl] amino}-6-oxoheptyl) pentanamide as a molecule which can be used for the inhibition of ZIKV NS2B-NS3 serine protease. Keywords: Zika virus, NS2B-NS3 protease, Inhibition, In silico. INTRODUCTION Zika virus (ZIKV) is a member of genus Flavivirus belonging to the family Flaviviridae of ribonucleic acid (RNA) viruses. Previously ZIKV was considered as a rare and mild pathogen for humans [1]. Recently, this mosquito-borne Flavivirus has triggered global public health crisis, linking ZIKV infection to fetal microcephaly and Guillain-Barre syndrome and other neurological complications in adults like acute myelitis and meningoencephalitis [2-5]. The World Health Organization has declared ZIKA a Public Health Emergency of International Concern [6], as there are no vaccines or antiviral drugs available for treatment or protection from the virus. Dengue virus (DENV), West Nile virus (WNV), yellow fever virus, tick-borne encephalitis virus, and Japanese encephalitis virus (JEV) are other flaviviruses that are important human pathogens besides ZIKV [7,8]. ZIKV has ~10.7-kB single- stranded RNA genome of positive polarity and encodes a single polyprotein of about 3,000 amino acids. During viral replication, this polyprotein is cleaved by host cell proteases (Signals, furin) into three structural proteins (Capsid, membrane, and envelope proteins) that are involved in viral particle assembly and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) responsible for viral replication, virion assembly and evasion from the host defense mechanism [7]. All cytoplasmic cleavages, inclusive of junctions between NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5 proteins and within the capsid, NS2A and NS4A proteins are carried out with NS2B-NS3 protease [7,8]. The Flavivirus NS2B-NS3 protease is essential for the virus replicated and thus constitutes an important and ideal target for antiviral drug development [9]. Suppression of immune responses by cleavage of a stimulator of interferon genes by NS2B-NS3 protease is also observed in DENV [10,11], it also triggers apoptosis via activating caspases in WNV [12] and starts neurotropic pathogenesis by inhibition of activator protein 1 in JEV [13]. Similar to other Flavivirus proteases, ZIKV consists of genome size of around 11 KB [14]. With one open reading frame which codes a polyprotein that further cleaved into structural proteins and nonstructural (NS) proteins, i.e., NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 [15]. NS3 is a multi-domain protein with RNA triphosphatase (NS3 RTpase) and RNA helicase (NS3 hell) activities while NS5 consist of an N-terminal methyltransferase domain and RNA polymerase (NS5 RdRp) [16-18]. According to Potapova et al. (2012) and Shiryaev et al. (2011) [19,20], the pathogenic properties of encephalitis virus are due to NS3 polymerase. ZIKV protease consists of the N-terminal domain of NS3, which is a chymotrypsin-like serine protease carrying an absolutely conserved triad His51, Asp75 and Ser135, NS2B is membrane bound and serves as a cofactor essential for folding and catalysis [21,22]. It has been reported that a construct comprising of ~ 185 residues of NS3 and ~ 40 hydrophilic residues of NS2B, covalently linked via a Gly4-Ser-Gly4 sequence, displays strong peptidolytic activity [23]. Potential therapeutic approach is to inhibit NS2B-NS3 protease, responsible for viral replication. Docking technique predicts the orientation of one molecule to second during binding to form a stable complex. Docking studies identify different parameters and structural features important for binding predictions during in silico screening, which helps in © 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2017.v10i5.17286 Research Article