Abdo A. Elfiky

Zika viral polymerase inhibition using anti‐HCV drugs both in market and under clinical trials

In the last few months, a new Zika virus (ZIKV) outbreak evolved in America. In accordance, World Health Organization (WHO) in February 2016 declared it as Public Health Emergency of International Concern (PHEIC). ZIKV infection was reported in more than 60 countries and the disease was spreading since 2007 but with little momentum. Many antiviral drugs are available in market or in laboratories under clinical trials, could affect ZIKV infection. In silico docking study were performed on the ZIKV polymerase to test some of Hepatitis C Virus (HCV) drugs (approved and in clinical trials). The results show potency of almost all of the studied compounds on ZIKV polymerase and hence inhibiting the propagation of the disease. In addition, the study suggested two nucleotide inhibitors (IDX‐184 and MK0608) that may be tested as drugs against ZIKV infection. J. Med. Virol. 88:2044–2051, 2016.

Correlation to Protein Conformation of Wide-Angle X-ray Scatter Parameters

In the last decade, several studies have reported that Wide-Angle X-ray Scattering (WAXS) from protein in solution contains valuable information about protein secondary and tertiary structures. Nevertheless, the use of such information will remain limited until a clear understanding of the correlation between protein structural elements and WAXS profile regions is established. In this work, large number of possible protein conformations is generated using comparative modeling (LOOPP & PHYRE servers) of nine different proteins representing six main protein classes (SCOP database). After model validation (SAVES server), protein structural elements of the selected models are retrieved (Swiss PDB Viewer & VORONOIA) and their corresponding WAXS profiles are generated (CRYSOL). The correlations between seven elements of protein structure (alpha helix, beta sheet and random coil content, alpha to beta ratio, alpha to random coil ratio, average packing density and number of residues) and seven WAXS profile parameters (Full Width at Half Maximum of two main scattering peaks of interest, their areas, positions and ratio of intensities) are investigated. Results revealed high (up to 0.75) and moderate (0.30–0.50) correlations between some of the suggested profile parameters and investigated protein structural elements indicating that these parameters represent a useful probe of protein conformation. Moreover, a high observed correlation between the degree of fitting of model to reference structures and the degree of fitting of their corresponding WAXS profiles suggests that the latter can be used in experimental model validation.

Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses†

A number of human coronaviruses (HCoVs) were reported in the last and present centuries. Some outbreaks of which (eg, SARS and MERS CoVs) caused the mortality of hundreds of people worldwide. The problem of finding a potent drug against HCoV strains lies in the inability of finding a drug that stops the viral replication through inhibiting its important proteins. In spite of its limited efficacy and potential side effects, Ribavirin is extensively used as a first choice against HCoVs. Therefore, scientists reverted towards the investigation of different drugs that can more specifically target proteins. In this study, four anti‐HCV drugs (one approved by FDA and others under clinical trials) are tested against HCoV polymerases. Quantitative Structure‐Activity Relationship (QSAR) and molecular docking are both used to compare the performance of the selected nucleotide inhibitors to their parent nucleotides and Ribavirin. Both QSAR and molecular docking showed that IDX‐184 is superior compared to Ribavirin against MERS CoV, a result that was also reported for HCV. MK‐0608 showed a performance that is comparable to Ribavirin. We strongly suggest an in vitro study on the potency of these two drugs against MERS CoV.

Molecular dynamics simulation revealed binding of nucleotide inhibitors to ZIKV polymerase over 444 nanoseconds

In the year 2015, new Zika virus (ZIKV) broke out in Brazil and spread away in more than 80 countries. Scientists directed their efforts toward viral polymerase in attempt to find inhibitors that might interfere with its function. In this study, molecular dynamics simulation (MDS) was performed over 444 ns for a ZIKV polymerase model. Molecular docking (MD) was then performed every 10 ns during the MDS course to ensure the binding of small molecules to the polymerase over the entire time of the simulation. MD revealed the binding ability of four suggested guanosine inhibitors (GIs); (Guanosine substituted with OH and SH (phenyl) oxidanyl in the 2′ carbon of the ribose ring). The GIs were compared to guanosine triphosphate (GTP) and five anti‐hepatitis C virus drugs (either approved or under clinical trials). The mode of binding and the binding performance of GIs to ZIKV polymerase were found to be the same as GTP. Hence, these compounds were capable of competing GTP for the active site. Moreover, GIs bound to ZIKV active site more tightly compared to ribavirin, the wide‐range antiviral drug.