Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery

Abstract

Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current work, we aimed at the promising virus drug target, ZIKV NS3 protease and constructed a Pharmacophore Anchor (PA) model for the active site. The PA model reveals a total of 12 anchors (E, H, V) mapped across the active site subpockets. We further identified five of these anchors to be critical core anchors (CEH1, CH3, CH7, CV1, CV3) conserved across flaviviral proteases. The ZIKV protease PA model was then applied in anchor-enhanced virtual screening yielding 14 potential antiviral candidates, which were tested by in vitro assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC 50 values 4.7 µM and 0.4 µM, inhibiting the viral protease with IC 50 values 6.0 µM and 2.6 µM respectively. Additionally, the PA model anchors aided in the exploration of inhibitor binding mechanisms. In conclusion, our PA model serves as a promising guide map for ZIKV protease targeted drug discovery and the identified 'previr' FDA drugs are promising for anti-ZIKV treatments.

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses

“…A natural active compound derived from black tea, theaflavin-3,3′-digallate, with an IC 50 of 2.3 µM was identified [ 28 ]. Asunaprevir and Simeprevir were identified using the pharmacophore anchor model to have potent anti-ZIKV activities with IC 50 values 4.7 µM and 0.4 µM [ 11 ]. Szymon et al identified small molecule inhibitors of ZIKV protease with a low micromolar affinity for protease [ 29 ].…”

“…After ZIKV and DENV infection of the host cell, the viral RNA is translated into a long polyprotein that is cleaved by a viral protease to generate three structural proteins (capsid, pre-membrane, and envelope proteins) and several nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) that contribute to the formation of viral particles and replication of the viral genome [ 11 , 12 ]. The protease is an essential enzyme for viral replication and an attractive target for antiviral drug development [ 13 , 14 ].…”

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

“…Several strategies, such as high throughput screening (HTS), computation-guided drug design, and fragment based drug discovery have been applied to develop protease in-hibitors [129][130][131][132][133]. The available inhibitors have been reviewed thoroughly [10,33,117,[134][135][136][137][138][139].…”

NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

“…The studies were published in 2017 (5/14; 36%), 41,42,[45][46][47] 2018-2019 (3/14; 21%), 43,44,54 and 2020-2021 (6/14; 43%). [48][49][50][51][52][53] The antiviral activities of the identified compounds were analyzed based on their ability to inhibit the NS2B-NS3 pro complex through protein thermal exchange assays (2/14; 14%), 41,45 T A B L E 1 Summary of chemical structures and biological proprieties of compounds with inhibitory activity against ZIKV NS2B-NS3 pro | 447 fluorescent peptide substrate assay (9/14; 65%), 42,44,[46][47][48][49][50]53,54 X-ray (1/14; 7%), 43 and fluorescence resonance energy transfer (2/14; 14%). 51,52 The IC 50 values for the inhibition of ZIKV NS2B-NS3 pro ranged at 0.…”

“…Part of the intermolecular interactions between the enzyme and compounds did not have a well-defined chemical bond. [41][42][43][44][45][46][48][49][50][51][52][53][54] In this context, 12 studies described the intermolecular interactions, such as hydrogen and hydrophobic bonds, involved in the activity of the compounds. 41,43,44,[46][47][48][49][50][51][52][53][54] Five compounds (Table 1, Entries 4, 5, 6, 7, and 17) showed the ability to interact with a region called 2B53 in NS3 (5/17, 29%), which contains essential amino acid residues to bind to NS2B.…”