Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus

Abstract:Dengue fever is an acute viral infection caused by the mosquito of the Aedes genus, with the largest incidence in tropical and sub-tropical regions of the world. There are no specific treatments against the dengue virus, and only the symptoms resulting from the disease are treated. The NS3/NS2B serine protease enzyme is essential for the life cycle of the virus and a promising target for drug development against the virus. In this work, acrylamide derivatives obtained from the literature data were submitted to molecular modeling studies. According to the results of the molecular docking calculations and subsequent consensual analysis, which consists of a statistical treatment used to assign the same importance to the results from different programs, and visual inspection we selected three compounds, which make hydrogen bonds with the amino acid residues His51, Asp75, Ser135, Gly151 and Gly153. Thus, Molecular Dynamics simulations were performed with three selected ligands using the hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) method, which the semiempirical AM1 Hamiltonian was used to describe the QM part and the OPLS-AA force field as method of Molecular Mechanics . The Root Mean Square Deviation (RMSD) graphs showed that systems were stabilized in 10 ns. Also, through the contribution of individual residues we observed that key residues, such as Ser34, Trp50, Lys73 and Gly151, were responsible for stabilization of the complex in the active site of the dengue enzyme.Keywords: Dengue; acrylamides derivatives; NS3/NS2B serine protease enzyme; molecular docking; molecular dynamics. ResumoA dengue é uma doença infecciosa aguda transmitida pelo mosquito do gênero Aedes, sendo que as áreas de maior incidência no mundo são regiões tropicais e subtropicais. Não existem tratamentos específicos contra o vírus da dengue, sendo apenas tratados os sintomas decorrentes da doença. A enzima serino protease NS3/NS2B é essencial para o ciclo de vida do vírus e um alvo promissor para o desenvolvimento de fármacos contra o vírus. Neste trabalho foram estudados compostos derivados da acrilamida obtidos da literatura, no qual foram submetidos a estudos de modelagem molecular. De acordo com os resultados da docagem molecular e subsequente análise consensual, que consiste em um tratamento estatístico usado para atribuir a mesma importância para os valores de energia em diferentes programas de docagem, e visual foram selecionados três compostos que fizeram ligação de hidrogênio com os resíduos de aminoácidos His51, Asp75, Ser135, Gly151 e Gly153. Deste modo, simulações de dinâmica molecular foram realizadas com os três ligantes usando o método híbrido Mecânica Quântica/Mecânica Molecular (QM/MM -Quantum Mechanics/Molecular Mechanics), no qual o método semiempírico AM1 foi utilizado para descrever a parte de Química Quântica e o campo de força OPLS-AA como método de Mecânica Molecular. Através dos resultados obtidos pelo gráfico do RMSD (Raiz do Desvio Médio Quadrático -Root Mean Square Deviation) observou-se que o sist...

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“…40 Este procedimento é utilizado para minimizar possíveis erros, como a seleção de falsos positivos . 50 …”

Section: Resultsunclassified

Molecular Modeling Study of Acrylamides Derivatives as Inhibitors of the Dengue Virus Serine Proteases NS2/NS3B

et al. 2017

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“…The respective values scored for the compounds are then summed up in each program, and the final rank of the compounds that were best scored by different scoring functions is obtained. 22…”

Section: Accepted Manuscript Experimental Virtual Screenings and Cons...mentioning

confidence: 99%

In silico identification of novel allosteric inhibitors of Dengue virus NS2B/NS3 serine protease

Rocha²,

Pinheiro

et al. 2022

J Serb Chem Soc

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Although dengue is a disease that affects more than 100 countries and puts almost 400 million lives at risk each year, there is no approved antiviral in the treatment of this pathology. In this context, proteases are potential biological targets since they are essential in the replication process of this virus. In this study, a library of more than 3,000 structures was used to explore the allosteric inhibition of the NS2B/NS3 protease complex using Consensual Docking techniques. The results show four best ranked structures that were selected for molecular dynamics and free energy simulations. Our analysis corroborate with other studies (experimental and theoretical) presented in the literature. Thus, the computational approach used here proved to be useful for planning new inhibitors in the combat against Dengue disease.

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“…Um aliado dos produtos naturais para potencializa-lo como um possível fármaco, além de reduzir tempo e custo nos processos experimentais são os métodos computacionais. Dentre esses destacam-se os cálculos de Docagem Molecular e a Simulação de Dinâmica Molecular (DM), onde o primeiro é aplicado em diferentes estágios do processo de descoberta de drogas para prever a estrutura ancorada de um complexo ligante-receptor, bem como para calcular uma energia de ligação que pode ser usada para classificar moléculas diferentes de acordo com sua afinidade por um receptor (OKIMOTO et al, 2009;PINHEIRO et al, 2015)which plays an important role in the replication process of this virus. According to the results of the molecular docking calculations and subsequent consensual analysis, the best scored compounds showed interactions between hydrogen and residues of the catalytic triad as well as interactions with residues that guide ligands to the active site of the enzyme.…”

Section: Agradecimentosunclassified

Construção De Modelos Moleculares Com Materiais Alternativos Para O Ensino De Química

Piva¹,

Gibin²

2019

Atividades De Ensino E De Pesquisa Em Química

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Todo o conteúdo deste livro está licenciado sob uma Licença de Atribuição Creative Commons. Atribuição 4.0 Internacional (CC BY 4.0).O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais.

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Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus

Cited by 16 publications

References 66 publications

Molecular Modeling Study of Acrylamides Derivatives as Inhibitors of the Dengue Virus Serine Proteases NS2/NS3B

Molecular Modeling Study of Acrylamides Derivatives as Inhibitors of the Dengue Virus Serine Proteases NS2/NS3B

In silico identification of novel allosteric inhibitors of Dengue virus NS2B/NS3 serine protease

Construção De Modelos Moleculares Com Materiais Alternativos Para O Ensino De Química

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