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      In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2

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          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (M pro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that 30 compounds are capable of M pro deactivation as well as potentially lowering the efficiency of M pro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.

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          Highlights

          • •

            In silico evaluation of natural flavonoids and synthetic indole chalcones against homology modelled SARS-CoV-2 proteins (M pro, rdrp and S proteins) was carried out.

          • •

            Natural flavonoids and indole chalcones showed pharmacokinetic and ADMET properties.

          • •

            Out of 48 compounds, 30 compounds disrupted the activation/dimerization of M pro.

          • •

            Compounds supress viral replication and interacted with S protein RBD domain.

          • •

            Functional/structural roles of amino acid residues of SARS-CoV-2 proteins involved in binding interactions are discussed.

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          A pneumonia outbreak associated with a new coronavirus of probable bat origin

          Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)
          Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
          Article 0 comments Cited 10119 times – based on 0 reviews     Review now
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            A new coronavirus associated with human respiratory disease in China

            Fan Wu, Su Zhao, Bin Yu … (2020)
            Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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              Structure of Mpro from COVID-19 virus and discovery of its inhibitors

              Zhenming Jin, Xiaoyu Du, Yechun Xu … (2020)
              A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
              Article 0 comments Cited 1652 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Balaji Gowrivel Vijayakumar
                Deepthi Ramesh
                Annu Joji
                Jayadharini Jayachandra prakasan
                Tharanikkarasu Kannan
                Journal
                Journal ID (nlm-ta): Eur J Pharmacol
                Journal ID (iso-abbrev): Eur. J. Pharmacol
                Title: European Journal of Pharmacology
                Publisher: Elsevier B.V.
                ISSN (Print): 0014-2999
                ISSN (Electronic): 1879-0712
                Publication date PMC-release: 6 August 2020
                Publication date (Electronic): 6 August 2020
                Electronic Location Identifier: 173448
                Affiliations
                [1]Department of Chemistry, Pondicherry University, Kalapet, Puducherry, 605014, India
                Author notes
                [∗ ]Corresponding author. tharani.che@ 123456pondiuni.edu.in
                [1]

                Indicates equal contribution.

                Article
                Publisher ID: S0014-2999(20)30540-9 Publisher ID: 173448
                DOI: 10.1016/j.ejphar.2020.173448
                PMC ID: 7406432
                PubMed ID: 32768503
                SO-VID: 6b035b93-07ea-4edf-9f11-6510e637ad16
                Copyright © © 2020 Elsevier B.V. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 10 June 2020
                Date revision received : 29 July 2020
                Date accepted : 29 July 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: flavonoids,indole chalcones,sars-cov-2,in silico,covid-19,phytochemicals
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: flavonoids, indole chalcones, sars-cov-2, in silico, covid-19, phytochemicals

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