Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

• Published in: Journal of chemical information and modeling Vol. 62; no. 24; pp. 6825 - 6843
• Main Authors: Mottin, Melina, de Paula Sousa, Bruna Katiele, de Moraes Roso Mesquita, Nathalya Cristina, de Oliveira, Ketllyn Irene Zagato, Noske, Gabriela Dias, Sartori, Geraldo Rodrigues, de Oliveira Albuquerque, Aline, Urbina, Fabio, Puhl, Ana C., Moreira-Filho, José Teófilo, Souza, Guilherme E., Guido, Rafael V. C., Muratov, Eugene, Neves, Bruno Junior, Martins da Silva, João Hermínio, Clark, Alex E., Siqueira-Neto, Jair L., Perryman, Alexander L., Oliva, Glaucius, Ekins, Sean, Andrade, Carolina Horta
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-12-2022
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Assaying; Cell death; Collaboration; Epidemics; Humans; Machine learning; Molecular docking; Molecular Docking Simulation; Optimization; Peptide Hydrolases; Pharmaceutical Modeling; Protease; Protease inhibitors; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Public health; RNA polymerase; RNA-Dependent RNA Polymerase - metabolism; Viral Nonstructural Proteins - chemistry; Zika virus; Zika Virus - drug effects; Zika Virus - enzymology; Zika Virus Infection - drug therapy
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.2c00596

The Zika virus (ZIKV) is a neurotropic arbovirus considered a global threat to public health. Although there have been several efforts in drug discovery projects for ZIKV in recent years, there are still no antiviral drugs approved to date. Here, we describe the results of a global collaborative crowdsourced open science project, the OpenZika project, from IBM’s World Community Grid (WCG), which integrates different computational and experimental strategies for advancing a drug candidate for ZIKV. Initially, molecular docking protocols were developed to identify potential inhibitors of ZIKV NS5 RNA-dependent RNA polymerase (NS5 RdRp), NS3 protease (NS2B-NS3pro), and NS3 helicase (NS3hel). Then, a machine learning (ML) model was built to distinguish active vs inactive compounds for the cytoprotective effect against ZIKV infection. We performed three independent target-based virtual screening campaigns (NS5 RdRp, NS2B-NS3pro, and NS3hel), followed by predictions by the ML model and other filters, and prioritized a total of 61 compounds for further testing in enzymatic and phenotypic assays. This yielded five non-nucleoside compounds which showed inhibitory activity against ZIKV NS5 RdRp in enzymatic assays (IC50 range from 0.61 to 17 μM). Two compounds thermally destabilized NS3hel and showed binding affinity in the micromolar range (K d range from 9 to 35 μM). Moreover, the compounds LabMol-301 inhibited both NS5 RdRp and NS2B-NS3pro (IC50 of 0.8 and 7.4 μM, respectively) and LabMol-212 thermally destabilized the ZIKV NS3hel (Kd of 35 μM). Both also protected cells from death induced by ZIKV infection in in vitro cell-based assays. However, while eight compounds (including LabMol-301 and LabMol-212) showed a cytoprotective effect and prevented ZIKV-induced cell death, agreeing with our ML model for prediction of this cytoprotective effect, no compound showed a direct antiviral effect against ZIKV. Thus, the new scaffolds discovered here are promising hits for future structural optimization and for advancing the discovery of further drug candidates for ZIKV. Furthermore, this work has demonstrated the importance of the integration of computational and experimental approaches, as well as the potential of large-scale collaborative networks to advance drug discovery projects for neglected diseases and emerging viruses, despite the lack of available direct antiviral activity and cytoprotective effect data, that reflects on the assertiveness of the computational predictions. The importance of these efforts rests with the need to be prepared for future viral epidemic and pandemic outbreaks.