5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Computer-Aided Design, Synthesis, and Antiviral Evaluation of Novel Acrylamides as Potential Inhibitors of E3-E2-E1 Glycoproteins Complex from Chikungunya Virus

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Chikungunya virus (CHIKV) causes an infectious disease characterized by inflammation and pain of the musculoskeletal tissues accompanied by swelling in the joints and cartilage damage. Currently, there are no licensed vaccines or chemotherapeutic agents to prevent or treat CHIKV infections. In this context, our research aimed to explore the potential in vitro anti-CHIKV activity of acrylamide derivatives. In silico methods were applied to 132 Michael’s acceptors toward the six most important biological targets from CHIKV. Subsequently, the ten most promising acrylamides were selected and synthesized. From the cytotoxicity MTT assay, we verified that LQM330, 334, and 336 demonstrate high cell viability at 40 µM. Moreover, these derivatives exhibited anti-CHIKV activities, highlighting the compound LQM334 which exhibited an inhibition value of 81%. Thus, docking simulations were performed to suggest a potential CHIKV-target for LQM334. It was observed that the LQM334 has a high affinity towards the E3-E2-E1 glycoproteins complex. Moreover, LQM334 reduced the percentage of CHIKV-positive cells from 74.07 to 0.88%, 48h post-treatment on intracellular flow cytometry staining. In conclusion, all virtual simulations corroborated with experimental results, and LQM334 could be used as a promising anti-CHIKV scaffold for designing new drugs in the future.

          Related collections

          Most cited references103

          • Record: found
          • Abstract: found
          • Article: not found

          Software for molecular docking: a review.

          Molecular docking methodology explores the behavior of small molecules in the binding site of a target protein. As more protein structures are determined experimentally using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, molecular docking is increasingly used as a tool in drug discovery. Docking against homology-modeled targets also becomes possible for proteins whose structures are not known. With the docking strategies, the druggability of the compounds and their specificity against a particular target can be calculated for further lead optimization processes. Molecular docking programs perform a search algorithm in which the conformation of the ligand is evaluated recursively until the convergence to the minimum energy is reached. Finally, an affinity scoring function, ΔG [U total in kcal/mol], is employed to rank the candidate poses as the sum of the electrostatic and van der Waals energies. The driving forces for these specific interactions in biological systems aim toward complementarities between the shape and electrostatics of the binding site surfaces and the ligand or substrate.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography.

            Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus that has caused widespread outbreaks of debilitating human disease in the past five years. CHIKV invasion of susceptible cells is mediated by two viral glycoproteins, E1 and E2, which carry the main antigenic determinants and form an icosahedral shell at the virion surface. Glycoprotein E2, derived from furin cleavage of the p62 precursor into E3 and E2, is responsible for receptor binding, and E1 for membrane fusion. In the context of a concerted multidisciplinary effort to understand the biology of CHIKV, here we report the crystal structures of the precursor p62-E1 heterodimer and of the mature E3-E2-E1 glycoprotein complexes. The resulting atomic models allow the synthesis of a wealth of genetic, biochemical, immunological and electron microscopy data accumulated over the years on alphaviruses in general. This combination yields a detailed picture of the functional architecture of the 25 MDa alphavirus surface glycoprotein shell. Together with the accompanying report on the structure of the Sindbis virus E2-E1 heterodimer at acidic pH (ref. 3), this work also provides new insight into the acid-triggered conformational change on the virus particle and its inbuilt inhibition mechanism in the immature complex.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Chikungunya: a re-emerging virus.

              In the past decade, chikungunya--a virus transmitted by Aedes spp mosquitoes--has re-emerged in Africa, southern and southeastern Asia, and the Indian Ocean Islands as the cause of large outbreaks of human disease. The disease is characterised by fever, headache, myalgia, rash, and both acute and persistent arthralgia. The disease can cause severe morbidity and, since 2005, fatality. The virus is endemic to tropical regions, but the spread of Aedes albopictus into Europe and the Americas coupled with high viraemia in infected travellers returning from endemic areas increases the risk that this virus could establish itself in new endemic regions. This Seminar focuses on the re-emergence of this disease, the clinical manifestations, pathogenesis of virus-induced arthralgia, diagnostic techniques, and various treatment modalities. Copyright © 2012 Elsevier Ltd. All rights reserved.
                Bookmark

                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                30 June 2020
                July 2020
                : 13
                : 7
                : 141
                Affiliations
                [1 ]Laboratory of Medicinal Chemistry, Pharmaceutical Sciences Institute, Federal University of Alagoas, Maceió 57072-970, Brazil; gabrielfelipepassos@ 123456gmail.com (G.F.S.P.); matheus_gabriel199@ 123456hotmail.com (M.G.M.G.); jotaaraujo2004@ 123456gmail.com (J.X.d.A.-J.)
                [2 ]Center of Analysis and Research in Nuclear Magnetic Resonance, Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceió 57072-970, Brazil; thiago.aquino@ 123456iqb.ufal.br
                [3 ]Immunoregulation Research Group, Laboratory of Research in Virology and Immunology, Institute of Biological and Health Sciences, Federal University of Alagoas, Maceió 57072-970, Brazil; stephanniemaia92@ 123456gmail.com (S.J.M.d.S.); j.p.monteirocavalcante@ 123456gmail.com (J.P.M.C.); elane.santos@ 123456icbs.ufal.br (E.C.d.S.); enio.bassi@ 123456icbs.ufal.br (Ê.J.B.)
                Author notes
                [* ]Correspondence: edeildo.junior@ 123456iqb.ufal.br ; Tel.: +55-87-9-9610-8311
                Author information
                https://orcid.org/0000-0003-1104-0203
                https://orcid.org/0000-0002-4000-700X
                https://orcid.org/0000-0002-5959-4654
                https://orcid.org/0000-0002-7956-5746
                Article
                pharmaceuticals-13-00141
                10.3390/ph13070141
                7407227
                32629969
                118001e6-4a6f-4c0a-b399-0a7ca6f8f176
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 May 2020
                : 25 June 2020
                Categories
                Article

                virtual screening,acrylamides,chikungunya virus,antiviral,molecular docking,e3-e2-e1 glycoproteins complex

                Comments

                Comment on this article