Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus - PubMed (original) (raw)

Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus

Maheswata Sahoo et al. Genomics Inform. 2016 Sep.

Abstract

Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3) protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of -5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H)-one) was found to interact with NS3 protein with binding energy of -7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection.

Keywords: NS3 protein; drug design; flavivirus; high throughput screening methods; zika virus.

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Figures

Fig. 1

Fig. 1. (A) Three-dimensional structure of predicted nonstructural 3 (NS3) protein model of Zika virus (ZIKV). (B) Ramachandran plot of predicted NS3 model. (C) ProSA-web Z-scores of all protein chains in Protein Data Bank determined by X-ray crystallography and nuclear magnetic resonance spectroscopy with respect to their length. The Z-score of NS3 was present in that range represented in dot. (D) Energy plot for the predicted NS3 protein of ZIKV. (E) ERRAT plot for residue-wise analysis of homology model. aOn the error axis, two lines are drawn to indicate the confidence with which it is possible to reject regions that exceed that error value.

Fig. 2

Fig. 2. Molecular docking complex of berberine with nonstructural 3 (NS3) protein of Zika virus.

Fig. 3

Fig. 3. Chemical structure of 10 best lead molecules: ZINC53047591 (A), ZINC13510840 (B), ZINC19705600 (C), ZINC19711173 (D), ZINC25634061 (E), ZINC98342354 (F), ZINC02974658 (G), ZINC04086851 (H), ZINC98342344 (I), ZINC02974656 (J), and known inhibitor berberine: ZINC03779067 (K).

Fig. 4

Fig. 4. Docking interaction structure of 10 best lead molecules and known inhibitor berberine along with hydrogen bonds: ZINC53047591 (A), ZINC13510840 (B), ZINC19705600 (C), ZINC19711173 (D), ZINC25634061 (E), ZINC98342354 (F), ZINC02974658 (G), ZINC04086851 (H), ZINC98342344 (I), ZINC02974656 (J), and berberine: ZINC03779067 (K).

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