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© 2022 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents.

Details

Title
A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B/NS3 from Dengue Virus
Author
da Costa, Renato A 1 ; João A P da Rocha 2 ; Pinheiro, Alan S 3   VIAFID ORCID Logo  ; Andréia do S S da Costa 3 ; Elaine C M da Rocha 2 ; Silva, Rai C 4   VIAFID ORCID Logo  ; Arlan da S Gonçalves 5 ; Santos, Cleydson B R 6   VIAFID ORCID Logo  ; Davi do S B Brasil 3 

 Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém 66075-110, PA, Brazil; [email protected] (A.S.P.); [email protected] (A.d.S.S.d.C.); [email protected] (D.d.S.B.B.); Federal Institute of Education, Science and Technology of Pará Campus Castanhal, Castanhal 68740-970, PA, Brazil 
 Federal Institute of Education, Science and Technology of Pará—Campus Bragança, Bragança 68600-000, PA, Brazil; [email protected] (J.A.P.d.R.); [email protected] (E.C.M.d.R.) 
 Graduate Program in Science and Environment, Institute of Exact and Natural Sciences, Federal University of Pará (UFPA), Belém 66075-110, PA, Brazil; [email protected] (A.S.P.); [email protected] (A.d.S.S.d.C.); [email protected] (D.d.S.B.B.) 
 Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14040-901, SP, Brazil; [email protected] 
 Federal Institute of Education, Science and Technology of Espírito Santo, Vila Velha 29106-010, ES, Brazil; [email protected] 
 Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil; [email protected] 
First page
4118
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
14203049
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2686187657
Copyright
© 2022 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 (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.