New Binding Site Conformations of the Dengue Virus NS3 Protease Accessed by Molecular Dynamics Simulation

Almeida, Hugo de; Bastos, Izabela Marques Dourado; Ribeiro, Bergmann Morais; Maigret, Bernard; Santana, Jaime M.

doi:10.1371/journal.pone.0072402

Cited by 20 publications

(17 citation statements)

References 65 publications

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“…7 Na Tabela 1 observa-se que as interações mais frequentes e significativas foram feitas com resíduos de aminoácidos polares, tais como His51, Asp75 e Ser135, que fazem parte dos subsítios S1' e S2 e que compõem a tríade catalítica. As interações por ligação de hidrogênio com a enzima ocorrem nas regiões nucleofílicas dos ligantes, onde estão presentes os átomos de nitrogênio e oxigênio.…”

Section: Percentual De Inibiçãounclassified

“…7,60 A conformação da alça de inibição complementar ao sítio ativo da enzima a ser inibida permite uma ligação bastante forte entre a enzima e o inibidor. Assim, os resultados de modelagem molecular foram capazes de propor e entender o modo de interação entre os compostos derivados de acrilamida e a enzima serino protease NS3/NS2B do DENV.…”

Section: Percentual De Inibiçãounclassified

“…[3][4][5][6] A maioria das mortes ocorre após a evolução da doença em febre hemorrágica e síndrome de choque da dengue. 7 O RNA genômico do vírus apresenta três proteínas estruturais (C, prM e E) e sete proteínas não estruturais (NS1, NS2A, NS2B, NS3, NS4A, NS4B e NS5), que causam a produção de novos vírus ao infectar as células. 8 Sua tradução gera uma poliproteína, a qual é clivada por proteases do vírus e da célula hospedeira e a interação do RNA no complexo de replicação.…”

Section: Introductionunclassified

“…9 A NS3 é uma serino protease do tipo tripsina, sendo uma poliproteína multifuncional composta por um domínio helicase e um domínio protease, onde o domínio protease está na região N-terminal e o helicase na Cterminal. 7 A NS3 apresenta uma tríade catalítica constituída de His51, Asp75 e Ser135. Embora a tríade esteja inteiramente constituída dentro dos subsítios da NS3, a protease funcional requer a presença do cofator NS2B, visto que reações que contém a NS3 protease sem o cofator são incapazes de promover atividade.…”

Section: Introductionunclassified

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

et al. 2017

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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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Section: Percentual De Inibiçãounclassified

Section: Introductionunclassified

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

et al. 2017

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“…DENV has also emerged as an increasing fitness problem in the world for which no specialized drug is available in the market. The non-structural protein NS3 protease of DENV has already been recognized as a potential therapeutic target for the discovery and development of novel antiviral agents against DENV infection [8,17,22,23,36,37]. NS3 molecule of DENV is comprised of a protease (NS3pro) and a helicase (NS3hel) domain, where the NS3pro domain relies on a cofactor, NS2B for their catalytic action and serves as a center for the assembly of the DENV replication complex and also modulates viral pathogenesis and the host immune response [4,6,11,18,19].…”

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Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database

et al. 2016

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Dengue virus (DENV) has emerged as an increasing fitness problem in the world for which no specialized drug is available. The non-structural protein NS3 protease of DENV has already been recognized as a potential therapeutic target for the discovery and development of novel antiviral agents against DENV infections. In this study, we employed the virtual screening technique to explore the potent inhibitors of DENV NS2B/NS3pro from Traditional Chinese Medicine (TCM) database. Total 200 inhibitors from TCM against DENV NS3pro were screened and only five TCM compounds like eriodictyol 7-O-glucuronide, luteolin 8-C-beta-glucopyranoside, (-)-epicatechin-3-O-gallate, 6-O-trans-p-coumaroylgeniposide and luteolin-7-O-glucoside were selected for further analysis which showed binding energies, -7.000, -7.380, -7.380, -7.440 and -7.440 kcal/mol, respectively. The findings of this study suggest that these five TCM compounds can be considered as potent inhibitors for DENV NS2B/NS3pro for the development of anti-dengue drugs.

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Ligand Accessibility Insights to the Dengue Virus NS3‐NS2B Protease Assessed by Long‐Timescale Molecular Dynamics Simulations

et al. 2021

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Dengue is a tropical disease caused by the dengue virus (DENV), with an estimate of 300 million new cases every year. Due to the limited vaccine efficiency and absence of effective antiviral treatment, new drug candidates are urgently needed. DENV NS3‐NS2B protease complex is essential for viral post‐translational processing and maturation, and this enzyme has been extensively studied as a relevant drug target. Crystal structures often underestimate NS3‐NS2B flexibility, whereas they can adopt different conformational states depending on the bound substrate. We conducted molecular dynamics simulations (∼30 μs) with a non‐ and covalently bound inhibitor to understand the conformational changes in the DENV‐3 NS3‐NS2B complex. Our results show that the open‐closing movement of the protease exposes multiple druggable subpockets that can be investigated in later drug discovery efforts.

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New Binding Site Conformations of the Dengue Virus NS3 Protease Accessed by Molecular Dynamics Simulation

Cited by 20 publications

References 65 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

Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database

Ligand Accessibility Insights to the Dengue Virus NS3‐NS2B Protease Assessed by Long‐Timescale Molecular Dynamics Simulations

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