key: cord-0914670-qpq7i1ya authors: Elfiky, Abdo A. title: Novel guanosine derivatives against Zika virus polymerase in silico date: 2019-08-29 journal: J Med Virol DOI: 10.1002/jmv.25573 sha: 581f943755d091349cb6acce8a2ba50872432e82 doc_id: 914670 cord_uid: qpq7i1ya The Zika virus (ZIKV) outbreak, which started in the year 2015, is considered the fastest and most widely spread outbreak reported for this flavivirus. The polymerase domain of the NS5 protein has been targeted in other viral infections and is recognized as a suitable target in ZIKV infection. Different novel modified compounds against ZIKV NS5 have been tested in silico. A few structures have been solved for ZIKV polymerase and deposited in the protein data bank website. Two of these solved structures (with a resolution of less than 1.9 A) are used in this study to test the binding of 74 novel compounds in silico. Molecular docking is used to quantify the binding affinities of ZIKV polymerase and compare it to the hepatitis C virus NS5B. A total of 19 novel compounds revealed results that are either similar to or better than the physiological molecule, guanosine triphosphate. Water molecules are found to facilitate the binding of the compounds to ZIKV RNA‐dependent RNA polymerase (RdRp) structures. The presented 19 novel compounds represent good binders to ZIKV RdRp and could be suitable candidates for developing a new and effective anti‐ZIKV polymerase nucleotide inhibitor. Seventy years ago, in Uganda, the Zika virus (ZIKV) was reported for the first time. 1, 2 About six decades later, newer incidents of emergence recorded in Nigeria, Senegal, and Gabon. [3] [4] [5] Despite its spread, the reported ZIKV infections were not like the latest emerging outbreak in the year 2015 in Latin America. 6 ZIKV is transmitted through body fluids and sexually. A direct link between newborn microcephaly and pregnant women infection was confirmed in the year 2016. [7] [8] [9] [10] Mosquito bites are the main route of spread of ZIKV infections along with sexual intercourse. 11, 12 The mild symptomatic ZIKV infection can be easily detected in body fluids like blood urine and saliva. 10, 13 Severe neurological diseases and sterility are reported in some patients as the virus targets all cells of the nervous system. 14 The ZIKV genome is a single-stranded RNA that encodes a 3400 amino acid polyprotein, which is processed by viral and host proteases to ten functional proteins. 15 The nonstructural 5 (NS5) protein is the most widely conserved protein and has been targeted in previous viral infections like hepatitis C virus (HCV). [16] [17] [18] The ZIKV RNA-dependent RNA polymerase (RdRp) domain of the NS5 protein has been targeted by anti-HCV drugs (repurposing). 19 19, 23 Nucleotide inhibitors mimic the native nucleotides in their ability to selectively target the active site of NS5 to be added into the primer RNA strand. Once bound to the protein, nucleotide inhibitors block the polymerization process and cause protein inhibition. [24] [25] [26] Guanosine derivatives were studied against HCV polymerase and a candidate, IDX-184, was under the clinical trials phase IIb before this was halted due to a side effect in the year 2013. 18 This gave better results compared with the uridine derivative (sofosbuvir), adenine derivative (MK-0608), and the wide-range antiviral ribavirin against HCV and human coronaviruses in silico. 16, 18 Molecular modeling represents a successful method used to predict the drug/target binding potency and mode of interaction. Based on a suitable model, it can differentiate between active and inactive inhibitors and suggest new compounds (in silico screening). [27] [28] [29] [30] [31] A few solved structures have been deposited in the protein data bank recently for the ZIKV NS5 protein. [32] [33] [34] [35] [36] [37] In this study, the author used two structures with PDB codes 5U04 and 5WZ3 as a drug target due to their appropriate resolution (1.9 and 1.8 Å, respectively) compared with other solved structures of ZIKV NS5. AutoDock Vina was used as the docking calculation method after cross-docking with HCV NS5B RdRp. Seventy-four new compounds were tested in this study against ZIKV NS5 RdRp structures. These compounds were derivatives of the guanine nucleotide. Structures of the ligands are prepared using SCIGRESS 3.4 tools. 31 The modifications were based on previous work, where three groups of modifications were introduced in the 2′ position in the ribose ring of the guanosine derivative. 38 Structural geometry optimization was performed using the following scheme; classical mechanical geometry optimization (MM3 force field) followed by the semiempirical parameterization method 6 (PM6) and finally, quantum mechanical density functional theory using the B3LYP functional. All these calculations were performed on the 3.4 GHz intel core-i7 processor PC (12 GB RAM) using SCIGRESS 3.4 software. [39] [40] [41] [42] 2.2 | Target retrieval, preparation, and docking Seventy-four modified guanosine derivatives (see Table S1 ) were sketched and optimized using the same procedure of that of Elfiky. 38 The modified compounds were based on modifying the 2′-position of the ribose ring of the guanosine triphosphate (GTP). The addition of a bulky group at this position gave good results against HCV NS5B RdRp in previous studies. 38,48 AutoDock Vina implemented on SCIGRESS 3.4 software was used in this study to calculate the binding energies between the ligands and the target polymerase for both ZIKV and HCV. Figure 1A The interacting amino acids with the ligands are also listed in Table 1 with the number of water molecules that take part in the interactions. Some water molecules mediate the interaction by binding to both the ligand and protein binding pocket. Suggesting a potent inhibitor against ZIKV RdRp is the primary goal of this study, Figure 1 shows that almost all compounds have good binding energies to ZIKV polymerase that are comparable to that for HCV RdRp. For the groups I and III of the modifications, the docking scores of ZIKV are almost in the same range as HCV except for compound 7 in group III that has a bit higher docking score value Table S1 ). This implies the effectiveness of the modified compounds in competing for the active site of ZIKV polymerase. RdRp is suggested to be a suitable target for HCV and other viruses due to its vital role in the replication of the virus. Due to the conservation of the RdRp's active site, it is also targeted in ZIKV and other viral infections. Previous studies show that anti-HCV NS5B drugs are able to bind to ZIKV RdRp (repurposing trials) but with relatively lower affinity compared with HCV. In this study, the author presents 19 modified guanosine derivatives that show in silico effectiveness against ZIKV NS5 RdRp. Further experimental work is suggested to characterize these modifications further and apply it to the virus in vitro and in vivo assays. Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria Isolations and serological specificity Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses Zika virus outbreak on Yap Island, federated states of micronesia Zika virus in Gabon (Central Africa)-2007: a new threat from Aedes albopictus? Rapid spread of emerging Zika virus in the Pacific area Zika virus associated with microcephaly How relevant is sexual transmission of Zika virus Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia Molecular detection of Zika virus in blood and RNA load determination during the French Polynesian outbreak Zika virus, French polynesia, South pacific Probable non-vector-borne transmission of Zika virus Potential use of saliva samples to diagnose Zika virus infection Complementary mechanisms potentially involved in the pathology of Zika virus Molecular dynamics simulation revealed binding of nucleotide inhibitors to ZIKV polymerase over 444 nanoseconds Quantitative structure-activity relationship and molecular docking revealed a potency of antihepatitis C virus drugs against human corona viruses Molecular modeling and docking revealed superiority of IDX-184 as HCV polymerase inhibitor IDX-184 is a superior HCV direct-acting antiviral drug: a QSAR study Zika viral polymerase inhibition using anti-HCV drugs both in market and under clinical trials Zika virus: novel guanosine derivatives revealed strong binding and possible inhibition of the polymerase The FDA-approved drug sofosbuvir inhibits Zika virus infection WHO. Zika strategic response framework and joint operations plan 5U04 (B)). ZIKV RdRp is represented by the colored cartoon while the amino acids involved in the interactions are represented by lines and labeled by their three-letter code Discovery of potential Zika virus RNA polymerase inhibitors by docking-based virtual screening Applications of computer-aided approaches in the development of hepatitis C antiviral agents. Expert Opin Drug Discovery New approaches in the treatment of hepatitis C RNA-dependent RNA polymerases of picornaviruses: from the structure to regulatory mechanisms Molecular Modelling: Principles and Applications A knowledge-based scoring function for protein-ligand interactions: probing the reference state Solvated docking: introducing water into the modelling of biomolecular complexes AutoDock4 and Auto-DockTools4: automated docking with selective receptor flexibility Structural properties of metal-free apometallothioneins The structure of Zika virus NS5 reveals a conserved domain conformation Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5 A structural view of the RNA-dependent RNA polymerases from the Flavivirus genus Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase The crystal structure of Zika virus NS5 reveals conserved drug targets Announcing the worldwide protein data bank Novel guanosine derivatives as anti-HCV NS5b polymerase: a QSAR and Molecular Docking Study Density-functional thermochemistry. III. The role of exact exchange Molecular mechanics. The MM3 force field for hydrocarbons. 3. The van der Waals' potentials and crystal data for aliphatic and aromatic hydrocarbons Optimization of parameters for semiempirical methods. III. Extension of PM3 to Be Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements Further insights into the roles of GTP and the C terminus of the hepatitis C virus polymerase in the initiation of RNA synthesis AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading The PyMOL Molecular Graphics System, Version 1.7.6, V. Schrödinger, LLC Statistics for Managers using Microsoft Excel. 660. Upper Saddle River Schrödinger Release 2017-1: Maestro, Schrödinger, LLC Hepatitis C RNA-dependent RNA polymerase inhibitors: a review of structure-activity and resistance relationships; different scaffolds and mutations Water determines the structure and dynamics of proteins How to cite this article: Elfiky AA. Novel guanosine derivatives against Zika virus polymerase in silico The authors declare that there are no conflict of interests. http://orcid.org/0000-0003-4600-6240