Abdo A. Elfiky

Quantitative structure-activity relationship (QSAR) parameters are good indicators for the reactivity of direct-acting antiviral drugs. Since molecular structure is related to molecular function, careful selection of molecular substitutions will result in more drugs that are potent. In this work, QSAR parameters are selected in order to compare the four drugs used as nucleotide inhibitors (NIs) for non-structural 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). These drugs are: ribavirin (widely used over the last 20 years), sofosbuvir (approved on December 2013 by FDA), and finally IDX-184 and R7128 (phase IIb of clinical trial drugs). The nucleotide analogues uracil (U), guanine (G), and cytosine (C) from which these drugs are fabricated are also compared to that group of drugs. QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs. It also shows that NIs are always more reactive than their parent nucleotide. © 2016 Springer Science+Business Media New York.

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. © 2016 Wiley Periodicals, Inc.

2'-Methylguanosine prodrug (IDX-184), Phosphoramidate prodrug (Sofosbuvir), Diisobutyryl prodrug (R7128) are Hepatitis C Virus (HCV) Non-Structural 5B (NS5B) RNA dependent RNA polymerase (RdRp) Nucleoside Inhibitors (NI) that are currently in clinical trials. The activated forms of these Direct Acting Antiviral (DAA) drugs act on NS5B RdRp. The present work utilizes a molecular modeling approach in order to study the interaction between the activated drugs and their parent nucleotides with the 12 amino acids constituting a 5 Å region surrounding the active site motif GDD for HCV subtypes 1a, 2b, 3b and 4a. The analysis of their interaction energies (calculated using semi-empirical method PM3) and their vibrational properties with the polymerase suggests that their inhibitory performance likely to be more potent than native nucleotides and Ribavirin (up to date antiviral therapy). Copyright © 2015 American Scientific Publishers.

This study is an attempt to improve the biological activity of boceprevir, an important HCV-NS3 protease inhibitor. This is performed through the suggestion of 8 modified compounds of boceprevir and testing their biological activity in silico. At PM3 level of theory, the electronic and Quantitative Structure Activity Relationship (QSAR) descriptors of the suggested compounds are calculated. Based on the values of these descriptors, the proposed compound 7 (with fluorinated sulfonamide at position R1, 1,3-dithiolane ring at position R2 and cyclopropane at position R3) has better biological activity as NS3 protease inhibitor than unmodified boceprevir. Copyright © 2015 American Scientific Publishers.

This work investigates the possibility of improving the biological activity of Telaprevir; an HCV NS3 protease inhibitor. This is carried out through the suggestion of 11 modified compounds of Telaprevir and calculating their electronic and Quantitative Structure Activity Relationship (QSAR) parameters using molecular modeling via PM3 method. Results show that the compound number 6 (with 1,3- dithiolane ring at position R2) has more favorable electronic and QSAR parameters compared to Telaprevir. Therefore, this modified compound would be considered as a promising novel HVC NS3 protease inhibitor. © 2014 American Scientific Publishers.

The current available treatment for hepatitis C virus (HCV) - the causative of liver cirrhosis and development of liver cancer - is a dual therapy using modified interferon and ribavirin. While this regimen increases the sustained viral response rate up to 40-80 % in different genotypes, unfortunately, it is poorly tolerated by patients. PSI-7977, a prodrug for PSI-7409, is a Non-Structural 5b (NS5b) polymerase nucleoside inhibitor that is currently in phase III clinical trials. The activated PSI-7977 is a direct acting antiviral (DAA) drug that acts on NS5b polymerase of HCV through a coordination bond with the two Mg+2 present at the GDD active site motif. The present work utilizes a molecular modeling approach for studying the interaction between the activated PSI-7977 and the 12 amino acids constituting a 5 Å region surrounding the GDD active triad motif for HCV genotypes 1a, 2b, 3b and 4a. The analysis of the interaction parameters suggests that PSI-7977 is probably a better DAA drug for HCV genotypes 1a and 3b rather than genotypes 2b and 4a. © 2013 Springer Science+Business Media New York.

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. © 2010 Springer Science+Business Media, LLC.