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Discovery of Novel Natural Flavonoids As Potent Antiviral Candidates

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Discovery of Novel Natural Flavonoids As Potent Antiviral Candidates Medical Hypotheses 132 (2019) 109359 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Discovery of novel natural flavonoids as potent antiviral candidates against hepatitis C virus NS5B polymerase T ⁎ Farideh Badichi Akhera,c, , Abdolkarim Farrokhzadehb,c, Pritika Ramharackc, ⁎ Letitia Shunmugamc, Fanie R. Van Heerdenb, Mahmoud E.S. Solimanc, a Department of Computer Science, University of Cape Town, Cape Town 7701, South Africa b School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Pietermaritzburg 3209, South Africa c Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa ARTICLE INFO ABSTRACT Keywords: The non-structural 5B (NS5B) polymerase of hepatitis C virus (HCV) is an attractive target for antiviral inter- Hepatitis C virus (HCV) vention. Quercetagetin (Que) is a natural flavonoid, which has been exhibited to have anti-HCV property Quercetagetin through inhibition of RNA binding to NS5B. The last few decades have witnessed a growing interest in the Natural compound extraction of natural flavonoids with a plethora of different biological activities. Considering the high ther- MD simulation apeutic potential of Que, the aim of this study is to explore wide structure entities with potent activity using Que Binding free energy as a prototype. A virtual screen protocol involving docking and molecular dynamics has been performed to examine the potency of forty-three natural flavonoids which recently extracted from plants for inhibition of NS5B. During two screening stages, two compounds 24 and 41 were identified to have more favorable binding affinity to NS5B as compared to Que. The comparative analysis showed that there is a significant difference in the binding free energy of Que and 41 (ΔΔGbind = −11.17 kcal/mol). It was revealed that van der Waals (vdW) interaction drives the binding process of both 24 and 41 and plays an important role in increasing their activities relative to Que. PHE162 serves as a crucial residue in both the NS5B-24 and NS5B-41 systems, contributing the most vdW energy by π-π interaction, suggesting that aromatic interactions are critical for the binding of 24 and 41 to NS5B. Moreover, hydrogen bond analysis indicates that the hydrogen bonds formed by LYS98, THR137, ASP164 and ARG168, can play important roles in the increased binding affinity of 41 to NS5B relative to Que. The findings of this study will provide useful structure-activity relationship (SAR) guidelines for the design of novel inhibitors with improved/enhanced therapeutic activities in the treatment of hepatitis C. Introduction Viral polymerases are essential components to the life cycle of any given virus. They initiate important roles that facilitate the con- Originally discovered in 1989, Hepatitis C Virus (HCV) was ex- sequential procession of viral replication and proper transcription of the perimentally proclaimed as the causative agent of hepatitis C [1,2]. genome of interest. Consequently, for this reason, viral polymerases Classified as a positive single-stranded RNA virus, HCV belongs to the present as a promising target for the design and development of potent Flaviviridae family within the Hepacivirus genus [3,4]. According to antiviral therapies within industries focusing on pharmaceutical and the World Health Organization (WHO), an indicative estimation con- medicinal chemistry [6]. The non-structural 5B (NS5B) polymerase has cluding a number close to 180 million individuals represents the extent been positively identified as a 55–66 kDa protein and is indefinitely to which the HCV infection has disseminated [4,5]. This disease may positioned at the C-terminus of the HCV genome. In 1999, the crystal resolve through utilization of market-available pharmaceutical drugs structure of NS5B was successfully documented [7] and revealed a such as ribavirin and PEGylated IFN however atleast 80% of the in- right-handed configuration accompanied by three intercalating sub- flicted individuals will advance to chronic HCV. In due course, poor domains referred to as the finger, palm and thumb domains [6].Ona prognosis progressively culminates into grievous hepato-related dis- complete scale, the entire NS5B structure is composited of approxi- eases including fibrosis, cirrhosis, and hepatocellular carcinomas [5]. mately 590 amino acids [8,9]. ⁎ Corresponding authors at: Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa. E-mail addresses: [email protected] (F.B. Akher), [email protected] (M.E.S. Soliman). https://doi.org/10.1016/j.mehy.2019.109359 Received 18 May 2019; Received in revised form 28 July 2019; Accepted 11 August 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved. F.B. Akher, et al. Medical Hypotheses 132 (2019) 109359 Fig. 1. 2D (a) and 3D (b) structure of Quercetagetin (Que). Fig. 2. The structure of compounds considered for the MD simulation. Table 1 The finally equilibrated values of RMSD (FE-RMSD) for each system. FE-RMSD (Å) Regions Que522243941 Protein 0.87 0.86 0.90 1.15 1.05 1.04 Active site 0.84 0.80 0.62 0.57 0.99 0.41 The values in parenthesis correspond to the active site residues backbone Cα atoms. preventing HCV replication and maturation [12–14]. Another note- worthy HCV NS5B inhibitor is dasabuvir, which actively prohibits RNA synthesis by binding to the polymerase thus impeding appropriate ex- ecution of viral replication [15]. Even though these HCV inhibitors possess great potency and high efficacy, the unprecedented evolution of the virus has led to a surge generation of genetic variations within the genome. As a result, HCV has developed a resistance against the current drugs. Moreover, high costs and induction of several undesirable side Fig. 3. Plots of RMSD for Cα atoms (Å) with respect to the initial structure vs effects have rendered DAAs unfavourable in the treatment of HCV [2]. simulation time (ns) for all the complexes 1–6. Flavonoids are notoriously known as a group of natural compounds containing an expansive selection of phenolic structures. These natural Direct acting antiviral (DAA) drugs of HCV NS5B are readily substances are often isolated from flowers, plant components, vege- available for public consumption and can be categorised into two dis- tables and fruits [2]. Highly acknowledged as an ever-growing health tinctive categories: nucleoside inhibitors (NIs) and non-nucleoside in- benefit, flavonoids are now considered an indispensable asset in an hibitors (NNIs) [10]. The cataloguing of a drug into a specified group is assortment of disciplines concerning cosmetological, medicinal, phar- based on the drug’s structural similarities and mode of action [11].A maceutical and nutraceutical science. This attribution is mainly derived distinguished example of such an inhibitor is sofosbuvir, which binds from their anti-viral, anti-carcinogenic, anti-inflammatory and anti- directly to the RNA by disguising itself as part of NS5B, thereby oxidative properties in conjunction with the desirable capability of 2 F.B. Akher, et al. Medical Hypotheses 132 (2019) 109359 Table 2 Direct hydrogen bonds between NS5B and the inhibitors in the systems. Direct hydrogen bonds Complexes Donor acceptor distance (Å) Occupancy (%) NS5B-Que Que H1 O3 ASP559 OD1 2.62 96.65 Que H O2 ASP559 OD1 2.63 55.04 NS5B-5 –––– –– – NS5B-22 –––– –– – NS5B-24 24 H O3 HIE95 O 2.50 84.40 24 H2 O5 GLY283 O 2.76 61.90 ALA97 H N 24 O1 2.89 42.60 NS5B-39 39 H2 O4 ASP318 OD2 2.62 64.22 39 H1 O3 ASP318 OD1 2.76 42.93 NS5B-41 ARG168 HH12 NH1 41 O7 2.81 78.57 THR137 HG1 OG1 41 O5 2.76 52.54 ARG168 HH22 NH2 41 O7 2.84 50.44 41 H3 O8 LYS98 O 2.71 48.10 41 H2 O6 ASP164 OD1 2.63 39.53 Table 3 Calculated binding Free-Energy (in kcal/mol) of the Studied Complexes. Energy Complexes ΔEvdW ΔEele ΔGgas ΔGele,sol(GB) ΔGnonpol,sol ΔGsol ΔGbind NS5B-Que −32.90 (±0.23) −41.16 (±0.70) −74.05 (±0.60) 44.01 ( ± 0.70) −4.53 ( ± 0.01) 39.48 (±0.32) −34.58 (±0.36) NS5B-5 −40.64 (±0.18) −16.29 (±0.35) −56.92 (±0.42) 35.14 ( ± 0.35) −5.13 ( ± 0.02) 30.01 (±0.33) −26.91 (±0.20) NS5B-22 −42.71 (±0.16) −10.34 (±0.25) −53.04 (±0.29) 26.92 ( ± 0.20) −4.52 (±0.02) 22.40 (±0.19) −30.64 (±0.18) NS5B-24 −37.93 (±0.20) −20.68 (±0.46) −58.61 (±0.45) 27.56 ( ± 0.32) −4.65 ( ± 0.01) 22.91 (±0.32) −35.70 (±0.21) NS5B-39 −35.04 (±0.23) −57.64 (±0.66) −92.68 (±0.63) 72.68 (±0.56) −5.88 ( ± 0.02) 66.80 (±0.55) −25.89 (±0.33) NS5B-41 −51.60 (±0.23) −33.60 (±0.58) −85.20 (±0.51) 45.82 ( ± 0.42) −6.37 ( ± 0.01) 39.46 (±0.42) −45.75 (±0.25) modulating cellular enzyme activities [16]. The previous studies have Computational methods shown Silibinin, a major active constituent of Silymarin (molecules with a flavonoid part and a lignan part) extracted from milk, can po- Initial structure preparation tently reduce HCV RNA levels in infected patients when administered intravenously. Also, the flavonol Quercetagetin (Que, Fig. 1) has been The starting structure of HCV NS5B was obtained from the crystal recently identified to be the most potent non-nucleoside NS5B RdRp structure (PDB entry 4OOW). All crystal water molecules and bound inhibitor among the six flavonoid subfamilies tested [17]. Que acts inhibitor were deleted from the PDB file and missing residues were through inhibition of the RNA binding to the viral polymerase [17].
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