Browsing by Author "Yu, Guann-Yi"

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Pharmacophore anchor models of flaviviral NS3 proteases lead to drug repurposing for DENV infection
(2017-12-28)
Pathak, Nikhil
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Lai, Mei-Ling
;
Chen, Wen-Yu
;
Hsieh, Betty-Wu
;
Yu, Guann-Yi
Background: Viruses of the flaviviridae family are responsible for some of the major infectious viral diseases around the world and there is an urgent need for drug development for these diseases. Most of the virtual screening methods in flaviviral drug discovery suffer from a low hit rate, strain-specific efficacy differences, and susceptibility to resistance. It is because they often fail to capture the key pharmacological features of the target active site critical for protein function inhibition. So in our current work, for the flaviviral NS3 protease, we summarized the pharmacophore features at the protease active site as anchors (subsite-moiety interactions). Results: For each of the four flaviviral NS3 proteases (i.e., HCV, DENV, WNV, and JEV), the anchors were obtained and summarized into 'Pharmacophore anchor (PA) models'. To capture the conserved pharmacophore anchors across these proteases, were merged the four PA models. We identified five consensus core anchors (CEH1, CH3, CH7, CV1, CV3) in all PA models, represented as the "Core pharmacophore anchor (CPA) model" and also identified specific anchors unique to the PA models. Our PA/CPA models complied with 89 known NS3 protease inhibitors. Furthermore, we proposed an integrated anchor-based screening method using the anchors from our models for discovering inhibitors. This method was applied on the DENV NS3 protease to screen FDA drugs discovering boceprevir, telaprevir and asunaprevir as promising anti-DENV candidates. Experimental testing against DV2-NGC virus by in-vitro plaque assays showed that asunaprevir and telaprevir inhibited viral replication with EC50 values of 10.4 mu M & 24.5 mu M respectively. The structure-anchor-activity relationships (SAAR) showed that our PA/CPA model anchors explained the observed in-vitro activities of the candidates. Also, we observed that the CEH1 anchor engagement was critical for the activities of telaprevir and asunaprevir while the extent of inhibitor anchor occupation guided their efficacies. Conclusion: These results validate our NS3 protease PA/CPA models, anchors and the integrated anchor-based screening method to be useful in inhibitor discovery and lead optimization, thus accelerating flaviviral drug discovery.
Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
(2020-06-02)
Pathak, Nikhil
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Kuo, Yi-Ping
;
Chang, Teng-Yuan
;
Huang, Chin-Ting
;
Hung, Hui-Chen
Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barre 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 EC50 values 4.7 mu M and 0.4 mu M, inhibiting the viral protease with IC50 values 6.0 mu M and 2.6 mu M 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.