In Silico Designed Axl Receptor Blocking Drug Candidates Against Zika Virus Infection

Edita Sarukhanyan,Thomas Dandekar,Sergey Shityakov

doi:10.1021/acsomega.8b00223

Edita Sarukhanyan, Thomas Dandekar + Show 1 more

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https://doi.org/10.1021/acsomega.8b00223

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Abstract

After a large outbreak in Brazil, novel drugs against Zika virus became extremely necessary. Evaluation of virus-based pharmacological strategies concerning essential host factors brought us to the idea that targeting the Axl receptor by blocking its dimerization function could be critical for virus entry. Starting from experimentally validated compounds, such as RU-301, RU-302, warfarin, and R428, we identified a novel compound 2′ (R428 derivative) to be the most potent for this task amongst a number of alternative compounds and leads. The improved affinity of compound 2′ was confirmed by molecular docking as well as molecular dynamics simulation techniques using implicit solvation models. The current study summarizes a new possibility for inhibition of the Axl function as a potential target for future antiviral therapies.

Highlights

Zika virus (ZIKV) belongs to the family of flaviviruses, which was first isolated in 1947 from rhesus monkeys in the Zika forest of Uganda.[1−4] The ZIKV epidemic has drawn global attention after a large outbreak in Brazil in 2014, which spread to over 60 countries
Several labs reported that the Axl receptor may not play an important role in ZIKV infection.[24−27] for instance, Wang et al.[24] claim that the Axl-deficient mice show the same level of replication of ZIKV as nondeficient ones
To identify new compounds for Axl receptor inhibition, we looked at warfarin and R428, which are the Axl receptor inhibitors sufficiently validated in their action to be used in clinical trials.[21,22,39]

Summary

Introduction

Zika virus (ZIKV) belongs to the family of flaviviruses, which was first isolated in 1947 from rhesus monkeys in the Zika forest of Uganda.[1−4] The ZIKV epidemic has drawn global attention after a large outbreak in Brazil in 2014, which spread to over 60 countries. The virus can be transmitted through sexual contact[5−8] as well as from mother to fetus.[9−11] Clinical observations suggest that ZIKV, transmitted from an infected woman to a fetus, mainly, targets human neural progenitor cells (hNPCs) and impairs their development.[4] There are no established drugs or vaccines against ZIKV yet. As a fourth step Ekins et al suggest homology model development for ZIKV proteins similar to those that are used against dengue virus (DENV) treatment.[12] Later on, they proposed to understand the exact mechanism of action to screen the compounds with higher target specificity and, to test them on animals.[12]

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