Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT1A receptor ligands

Weber, Karen C.; Salum, Lívia B.; Honório, Káthia Maria; Andricopulo, Adriano D.; Silva, Albérico Borges Ferreira da

doi:10.1016/j.ejmech.2009.12.059

Cited by 30 publications

(45 citation statements)

References 36 publications

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“…A proper alignment can make molecules to be represented with comparable conformations and consistent orientations. Currently, there are three basic kinds of alignment methods: substructure based, pharmacophore based and docking based, and these (Brito et al, 2008;Liu et al, 2014;Vyas et al, 2014;Weber et al, 2010). In this study, substructure-based and docking-based methods were used to align the molecules, and the corresponding results were carefully compared in order to find the better method for model constructions.…”

Section: Alignment Rulesmentioning

confidence: 99%

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

et al. 2015

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In this paper, 65 small molecules of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) were aligned by two different alignment methods (substructure-based and docking-based alignment) for the construction of three-dimensional quantitative structureactivity relationship models. And the molecular descriptors were calculated by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Statistical parameters derived from the models using the above two different alignment methods showed that the docking-based CoMFA and CoMSIA models were better than the substructure-based models with both higher internal consistencies (q 2 of 0.727 and 0.698, respectively) and external predictive powers (r 2 pred of 0.906 and 0.940, respectively). According to the generated contour maps, several key structural features required for increasing the biological activity of compounds were achieved. Additionally, a docking study was also performed to explore the binding mechanisms of this series of compounds, and the obtained binding interactions are in agreement with the results of the contour maps. These structural-based and ligand-based computational studies can offer useful references for the further rational design of HIV-1 NNRTIs.

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Section: Alignment Rulesmentioning

confidence: 99%

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

et al. 2015

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“…Estratégias de VS por similaridade química ou modelos farmacofóricos permitem a investigação de conjuntos de dados com diversidade estrutural mais ampla do que aquela encontrada em estudos de QSAR. 37,42,44 Alguns exemplos ilustram a aplicação destas técnicas na identificação de novos esqueletos químicos (scaffold hopping). 40,45 Etapas de LBVS Em geral, os métodos de LBVS se fundamentam em estudos de similaridade ou em modelos construídos a partir de conjuntos de ligantes e não ligantes.…”

Section: Triagem Virtual Baseada Na Estrutura Do Liganteunclassified

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

Ferreira¹,

Oliva²,

Andricopulo³

2011

Quím. Nova

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Recebido em 16/1/11; aceito em 2/6/11; publicado na web em 26/7/11 INTEGRATING VIRTUAL AND HIGH-THROUGHPUT SCREENING: OPPORTUNITIES AND CHALLENGES IN DRUG RESEARCH AND DEVELOPMENT. High-throughput screening (HTS) and virtual screening (VS) are useful methods employed in drug discovery, allowing the identification of promising hits for lead optimization. The efficiency of these approaches depends on a number of factors, such as the organization of high quality databases of compounds and the parameterization of essential components of the screen process. This brief review presents the basic principles of the HTS and VS methods, as well as a perspective of the utility and integration of these drug design approaches, highlighting current opportunities and future challenges in medicinal chemistry.Keywords: high-throughput screening; virtual screening; drug design. INTRODUÇÃOA descoberta de novos fármacos é um grande desafio para a indústria farmacêutica moderna. Os altos investimentos na área de pesquisa e desenvolvimento (P&D) contrastam com o número de novos medicamentos que têm chegado ao mercado nos últimos anos. 1 Este complexo panorama tem forçado a adoção de novas estratégias com o objetivo de aumentar a eficiência do processo de P&D, tendo como alicerces as inovações científicas, tecnológicas e empresariais.Considerando-se o expressivo número de alvos biológicos (proteínas alvo) promissores para o planejamento de fármacos, as técnicas de triagem biológica automatizada em alta escala (HTS -high throughput screening) e de triagem virtual (VS -virtual screening) têm ocupado papel de destaque entre as estratégias modernas exploradas na identificação de novas substâncias bioativas. Desde o seu surgimento, a HTS tem sido amplamente utilizada pela indústria farmacêutica, propiciando a avaliação de milhões de compostos contra proteínas alvo. Embora esta estratégia tenha despertado a esperança de uma revolução na descoberta de substâncias bioativas, em pouco tempo as suas limitações ficaram evidentes. 2 A ocorrência de um número elevado de falso-positivos, identificados inicialmente como hits (termo em inglês para designar um novo ligante ou composto bioativo) nos ensaios bioquímicos em alta escala pode ser destacada como um dos grandes problemas. 3 Os múltiplos modos de interação ou mecanismos de ação apresentados pelos diferentes hits selecionados podem também ser mencionados como outros importantes obstácu-los. 4 Além disso, o número possível de compostos com propriedades fármaco-similar (drug-like) 5 é várias ordens de magnitude maior do que o número de compostos que pode ser analisado nos processos de HTS. Portanto, o planejamento das bases de dados de compostos é essencial, sendo que fatores como propriedades moleculares e físico-químicas, ou ainda a diversidade química, devem ser considerados. [6][7][8] Com os notáveis avanços da biologia estrutural e a disponibilidade de recursos computacionais de alto desempenho, a VS surgiu como importante alternativa à HTS. A VS é um método in silico ("computacional") empre...

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“…1 5-HT exerts its effects via 5-HT receptors, which can be classified into seven subfamilies, 5-HT 1 to 5-HT 7 . 2-7 Among them, 5-HT 1A R has drawn particular attention because of its important therapeutic potentials for anxiety [8][9][10][11] , depression 3, 12, 13 , cognition impairment 11,13 and other psychiatric syndrome. 3,14 The 5-HT 1A R agonists have also been found as effective treatments for neurological disorders (e.g.…”

Section: Introductionmentioning

confidence: 99%

Higher-Affinity Agonists of 5-HT_1AR Discovered through Tuning the Binding-Site Flexibility

Lian

Geng

et al. 2015

J. Chem. Inf. Model.

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Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ∼50-fold increase in receptor-binding affinity and ∼25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3).

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Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT1A receptor ligands

Cited by 30 publications

References 36 publications

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

Higher-Affinity Agonists of 5-HT_1AR Discovered through Tuning the Binding-Site Flexibility

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Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT1A receptor ligands

Cited by 30 publications

References 36 publications

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility

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Higher-Affinity Agonists of 5-HT_1AR Discovered through Tuning the Binding-Site Flexibility