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Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease
Akaberi, Dario Chinthakindi, Praveen K Båhlström, Amanda Palanisamy, Navaneethan Sandström, Anja Lundkvist, Åke Lennerstrand, Johan
Akaberi, Dario
Chinthakindi, Praveen K
Båhlström, Amanda
Palanisamy, Navaneethan
Sandström, Anja
Lundkvist, Åke
Lennerstrand, Johan
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2019-12-27
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Abstract
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as <b>9b</b>, was identified by <i>in silico</i> screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound <b>9b</b> formed a stable complex with ZIKV protease. Interaction analysis of compound <b>9b</b>'s binding pose from the cluster analysis of MD simulations trajectories predicted that <b>9b</b> mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound <b>9b</b> was found to inhibit ZIKV serine protease <i>in vitro</i> with IC<sub>50</sub> = 143.25 ± 5.45 µM, in line with the <i>in silico</i> results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds <b>9b</b> and <b>86</b> (a known panflavivirus peptide hybrid with IC<sub>50</sub> = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound <b>86</b> to be lower than that of <b>9b</b>, proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound <b>9b</b> represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.
Citation
Akaberi, D., Chinthakindi, P. K., Båhlström, A., Palanisamy, N., Sandström, A., Lundkvist, Å., & Lennerstrand, J. (2020). Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease. Journal of Biomolecular Structure and Dynamics, 38(18), 5526-5536. https://doi.org/10.1080/07391102.2019.1704882
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Taylor & Francis
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Journal of Biomolecular Structure and Dynamics
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Article
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en
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0739-1102
EISSN
1538-0254
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Scandinavian Society for Antimicrobial Chemotherapy