key: cord-0694731-nit5v1wg authors: Elfiky, Abdo A.; Mahdy, Samah M.; Elshemey, Wael M. title: Quantitative structure‐activity relationship and molecular docking revealed a potency of anti‐hepatitis C virus drugs against human corona viruses date: 2017-02-16 journal: J Med Virol DOI: 10.1002/jmv.24736 sha: 142699ba5f2be90b66f9e95fa87e9d8029fddc1e doc_id: 694731 cord_uid: nit5v1wg 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. 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. [2] [3] [4] [5] While SARS fatality rate was 8%, MERS fatality rate was 36% (by 9th of November 2016, the number of laboratory confirmed infections was 1813 and the number of reported deaths was 645). 2, 6 Six coronavirus strains were reported to be zoonotic (ie, transmission of infections from animals to humans is possible). [7] [8] [9] [10] [11] These human coronaviruses were 229E and NL63 (belonging to Alphacoronavirus) and OC43, HKU1, SARS, and MERS (belonging to Betacoronavirus). 5, 12 While the first four strains caused mild upper respiratory tract infections, like common cold, SARS and MERS both caused lower respiratory infections such as bronchitis, bronchiolitis, and pneumonia. 13, 3 It was reported that SARS CoV and MERS CoV were hosted in bat through palm civet cat and dromedary camel, respectively. 5, [14] [15] [16] Generally, coronaviruses are enveloped, positive-sense, singlestranded RNA (∼30 kb). Coronavirus genome is translated inside host cell into two groups of proteins; structural proteins, such as Spike (S), Nucleocapsid (N), Matrix (M) and Envelope (E), and non-structural proteins such as RNA dependent RNA polymerase (nsp12) and Helicase (nsp13). 17, 18 Coronaviruses enter host cells either through endosomal or non-endosomal pathways. 19 Polymerases have conserved active site aspartates that take part in nucleotidyl transfer in different organisms from viruses to humans. 26 The use of modified nucleotides to block the polymerization process was reported in the last two decades. The first FDA approved nucleotide inhibitor was Sofosbuvir (December 2013). Sofosbuvir was approved with Ribavirin and interferon or as interferon-free regimen. In addition, it was also approved in combination with other target protein inhibitors. 27, 28 Computer Aided Drug Design (CADD) is the utilization of computer software to mimic, visualize, and characterize the behavior of biological molecules. It often uses molecular modeling in conjunction with Quantitative Structure-Activity Relationship (QSAR) in order to test the reactivity of a ligand and its binding pattern into protein active site. 29, 30 Molecular docking is usually used in order to mimic the binding of a ligand into protein active site using a scoring function. More negative docking scores mean better binding of the drug to the active site of the target protein and hence, more inhibitory performance. 31 In this study, combined QSAR and molecular docking are utilized to evaluate the binding of some nucleotide polymerase inhibitors (Sofosbuvir, IDX-184, R7128, and MK-0608) to HCoV polymerase active site. 27, 32 These drugs are either FDA approved or under clinical trials. The study also compares the binding performance of these nucleotide inhibitors to that of native nucleotides and Ribavirin. This study utilizes the medicinal chemistry platform, SCIGRESS 3.0 (Fujitsu, Poland) 33 installed on Dell Precision T3500 workstation to examine the molecular docking of nucleotides (ATP, UTP, CTP, and GTP), their corresponding nucleotide inhibitors (MK-0608, Sofosbuvir, R7128, and IDX-184, respectively) and Ribavirin to different polymerases of HCoV strains. Structures of the nucleotides and nucleotide inhibitors are first sketched using SCIGRESS tools, 33 followed by geometry optimization using Molecular Mechanics force field (MM3 method). The structures are further optimized using semi-empirical Parameterization Method 6 (PM6 in water). Optimized structures are then examined by calculating the Infra-Red (IR) vibrational spectra using PM6 method in order to ensure that they are real (no negative vibrations). Finally, structures are quantum mechanically optimized according to the Density Functional Theory (DFT) using B88-LYP functional (DZVP basis set). This is followed by the calculation of IR vibrational spectra at the same level. At this stage, structures that are finally optimized become ready for QSAR and docking calculations. Similar to Tables 1 and 2 presents a comparison of each nucleotide analogue to its parent nucleotide and each drug to Ribavirin, but this time in terms of parameters describing structural reactivity instead of structural stability. Table 2 reveals that the nucleotide analogues are more reactive than their parent nucleotides (bold values in Table 2 ). This can be brought from the higher (better) values of dipole moment, Table 2 ). This can be recognized from the higher (better) values of dipole moment, surface accessible surface area, polarizability, and molar refractivity. Moreover, Log P shows that the studied compounds are more hydrophobic compared to parent nucleotides and ribavirin. This may facilitate passage through membranes. IDX-184 has the advantage of low toxicity due to its low concentration in blood. This emerges from its nature as a prodrug which converts to the active form inside its target cell, as reported for Hepatitis C Virus (HCV). 44 | 1045 Isolation of a novel Coronavirus from a man with pneumonia in Saudi Arabia Coronaviruses-drug discovery and therapeutic options Pathogenesis of Middle East respiratory syndrome coronavirus Emergence of MERS-CoV in the Middle East: origins, transmission, treatment, and perspectives Isolation and characterization of viruses related to the SARS Coronavirus from animals in southern China Middle East respiratory syndrome coronavirus (MERS-CoV) WHO Evidence supporting a zoonotic origin of human coronavirus strain NL63 Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event Evidence for an ancestral association of human coronavirus 229E with bats Evidence for zoonotic origins of Middle East respiratory syndrome coronavirus Mechanisms of zoonotic severe acute respiratory syndrome Coronavirus host range expansion in human airway epithelium Mechanisms of coronavirus cell entry mediated by the viral spike protein A previously undescribed coronavirus associated with respiratory disease in humans Coronaviruses: important emerging human pathogens Evidence for camel-to-human transmission of MERS coronavirus Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels a comparative serological study From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses SARS-beginning to understand a new virus Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Human aminopeptidase N is a receptor for human coronavirus 229E Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC Human Coronavirus HKU1 spike protein uses O-Acetylated sialic acid as an attachment receptor determinant and employs hemagglutinin-Esterase protein as a receptor-Destroying enzyme Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans Anti-HCV drugs in the pipeline Molecular modeling comparison of the performance of NS5b polymerase inhibitor (PSI-7977) on prevalent HCV genotypes Daclatasvir plus sofosbuvir for HCV infection: an oral combination therapy with high antiviral efficacy IDX-184 is a superior HCV directacting antiviral drug: a QSAR study The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors Integrative computational modeling of protein interactions 2′-Methylguanosine prodrug (IDX-184), phosphoramidate prodrug (Sofosbuvir), diisobutyryl prodrug (R7128) are better than their parent nucleotides and ribavirin in hepatitis C virus inhibition: a molecular modeling study Structural properties of metal-free apometallothioneins The EBI Search engine: providing search and retrieval functionality for biological data from EMBL-EBI Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega Deciphering key features in protein structures with the new ENDscript server The I-TASSER Suite: protein structure and function prediction Verification of protein structures: patterns of nonbonded atomic interactions Deviations from standard atomic volumes as a quality measure for protein crystal structures Substrate complexes of hepatitis C virus RNA polymerase (HC-J4): structural evidence for nucleotide import and de-novo initiation A comparative QSAR analysis and molecular docking studies of quinazoline derivatives as tyrosine kinase (EGFR) inhibitors: a rational approach to anticancer drug design Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design Water determines the structure and dynamics of proteins Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in healthy subjects Zika viral polymerase inhibition using anti-HCV drugs both in market and under clinical trials ACKNOWLEDGMENT Dr Wael A. Mohamed is appreciated for helpful discussions and suggestions.