Send Orders for Reprints to reprints@benthamscience.ae Letters in Drug Design & Discovery, 2019, 16, 000-000 1 RESEARCH ARTICLE 1570-1808/19 $58.00+.00 ©2019 Bentham Science Publishers Structure-based Identification of Potential Inhibitors of NS3 Protein of Zika virus Md Imam Faizan 1,5 , Abu Turab Naqvi 1 , Md. Imtaiyaz Hassan 1 , Mohd Abdullah 2,1 , Ayesha Tazeen 1 , Zoya Shafat 1 , Malik Hisamuddin 2,1 , Aftab Alam 1 , Shahnawaz Ali 1 , Sher Ali 1 , Anam Farooqui 1 , Abu Hamza 1 , Nazish Parveen 1 , Farah Deeba 1 , Anwar Ahmed 3,4 and Shama Parveen 1,* 1 Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India; 2 School of Life & Basic Sciences, Jaipur National University, Jaipur, Rajasthan, India; 3 Protein Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia; 4 Centre for Excellence in Biotechnology Research, Department of Biochemistry, College of Science, Kind Saud University, Riyadh, Saudi Arabia; 5 Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia A R T I C L E H I S T O R Y Received: February 12, 2018 Revised: August 13, 2018 Accepted: August 20, 2018 DOI: 10.2174/1570180815666180821105012 Abstract: Background: The re-emerging Zika virus has posed a serious threat to human health due to its association with the neurological disorders. The NS3 protein of Zika virus plays a pivotal role in the genome replication, and thus may prove to be a critical target for the drug designing studies. Objective: The present study was conceptualized to analyze the crystal structure of NS3 protein of Zika virus followed by the identification of it’s potential inhibitors. Methods: Crystal structure of the NS3 protein was evaluated in detail. Docking of the NS3 protein was done with 130 different ligands, including dengue virus inhibitors and their similar compounds along with some approved drugs. The drug likeliness properties were checked for non drug compounds. Results: Structural analysis of the NS3 protein revealed three important sites, namely ATP- and RNA- binding sites as well as a central cavity. The selected ten ligands (ZINC05487635, ZINC0092398, ZINC13345444, 4-methoxyphenyl 4-chloro-3-nitrobenzoate, Luteolin, Ivermectin, Suramin, Dasatinib, Panduratin A, and ARDP0009) showed a higher binding affinity for the NS3 protein, and good drug likeliness properties. Conclusions: These inhibitors could possibly act as potential lead molecules for future drug designing studies. Our present computational data is envisaged to be useful for gathering experimental evidences towards the development of potential therapeutic molecules against Zika virus infection. Keywords: Zika virus, NS3 protein, inhibitors, antiviral drugs, molecular docking, structure based drug design and discovery. 1. INTRODUCTION The Zika virus is transmitted by Aedes mosquito but re- cently sexual, prenatal and post-trans fusional routes have also been reported [1-4]. The symptoms of Zika fever in- clude rashes, headache, fever, myalgia, arthralgia & conjunc- tivitis. But recently the virus was shown to be associated with neuropathogenesis that resulted in Guillain–Barré syn- drome (GBS) and microcephaly that represented a newer threat to the mankind [5-7]. The virus is enveloped with sin- gle-stranded positive-sense RNA genome [8]. The 3,419 amino acids polyprotein formed by the genome is cleaved by cell proteases into three structural proteins namely capsid, pre-Membrane, and envelope, and seven non-structural pro- teins including NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 [9]. *Address correspondence to this author at the Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India; E-mail: shamp25@yahoo.com, sparveen2@jmi.ac.in The non-structural protein three (NS3) of Zika virus is a multifunctional protein which is primarily involved in the RNA replication and processing of polyprotein. Therefore, it is considered as a potential therapeutic target for inhibition of viral replication [10]. The NS3 protein of Zika virus is a bipartite enzyme with NS3 protease and NS3 helicase activi- ties [11]. The junctional cleavage of NS2B/NS3, NS2A/NS2B, NS4B/NS5 and NS3/NS4A are also performed by the NS3 protein. It forms a noncovalent complex with NS2B and performs the serine protease activity at its N- terminal region [12-14]. At the C-terminal region, it executes the nucleoside triphosphatase (NTPase) and RNA unwinding activities. It is also proposed that the NS3 protein is involved in the viral assembly. NS3 protein has three domains namely I, II and III [10, 15]. Similar to dengue virus NS3 protein, Zika virus NS3 also contains a catalytic serine protease triad that is composed of three different amino acids (His51, Asp75 and Ser135) [11]. The RNA-binding groove and ATP-binding site are the two most important regions of the NS3 protein that are needed for viral replication [15].