In silico approaches to Zika virus drug discovery

ABSTRACT

Introduction: After the WHO declared Zika virus (ZIKV) as a public health emergency of international concern, intense research for the development of vaccines and drugs has been undertaken, leading to the development of several candidates.

Areas covered: This review discusses the developments achieved so far by computational methods in the discovery of candidate compounds targeting ZIKV proteins, i.e. the envelope and capsid structural proteins, the NS3 helicase/protease, and the NS5 methyltransferase/RNA-dependent RNA polymerase.

Expert opinion: Research for effective drugs against ZIKV is still in a very early discovery phase. Notwithstanding the intense efforts for the development of new drugs and the identification of several promising candidates by using different approaches, including computational methods, so far only a few candidates have been experimentally tested. An important caveat of anti-flavivirus drug development is represented by the difficult of reproducing the in vivo microenvironment of the replication complex, which may lead to discrepancies between in vitro results and experimental evaluation in vivo. Moreover, anti-ZIKV drugs have the additional requirement of an excellent safety profile in pregnancy and ability to diffuse to different tissues, including the central nervous system, the testis, and the placenta.

KEYWORDS:

• Antiviral drugs
• drug design
• hit discovery
• NS2B-NS3 protease
• NS3 helicase
• NS5 MTase/RdRp
• virtual screening
• Zika virus

Article highlights

• ZIKV is an emerging mosquito-borne flavivirus that has rapidly spread in the recent years and caused unprecedented large human outbreaks, which, for the first time, revealed an etiological link with severe neurological complications, including Guillain-Barré syndrome and fetal microcephaly.

• Candidate ZIKV targets for antiviral drugs include the envelope glycoprotein E, the protease and helicase activities of NS2B-NS3, the methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) activities of NS5. Crystal structures of these targets have been solved.

• Several candidate anti-ZIKV compounds have been identified by in silico approaches, but only a few have been tested in vitro and in vivo to demonstrate efficacy and safety.

• Improvements in modeling the complex replication system of flaviviruses, including all viral and host components, would provide more accurate analyses of druggable binding sites and prediction of ligand-protein interaction by in silico approaches.

• Drugs for the treatment of ZIKV infection have specific requirements related to disease pathogenesis and target patient categories, which should be kept in mind in drug development.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was not funded.