Compound Selection and Filtering in Library Design

Lumley, James A.

doi:10.1002/qsar.200520136

Cited by 17 publications

(10 citation statements)

References 75 publications

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“…20 Dessa forma, o objetivo principal de uma triagem virtual é o de identificar os compostos de uma biblioteca que tenham maior probabilidade de se ligar a um alvo biológico. Com os avanços tecnológicos, a cada dia fica mais palpável a realização e aplicação prática dos conceitos de 33,34 propriedades estas que representam o principal gargalo no insucesso de candidatos a fármacos.…”

Section: Introductionunclassified

Virtual Screening Strategies in Drug Design

Rodrigues¹,

Mantoani²,

Almeida³

et al. 2012

Revista Virtual De Química

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Abstract:The development of virtual screening techniques represents a major advance in the current drug design era. Through several strategies, virtual screening is able to facilitate the selection of molecules with the desired chemical features to modulate the biological activity of the most attractive molecular targets currently available. From the simplest techniques, as the similarity search or molecular docking, to more complex strategies, including statistical methods and machine learning, the main goal of virtual screening is to improve the searching for molecules with the desired features required for becoming drug candidates, thus accelerating the continuous process of drug design. The aim of this review is to discuss the main virtual screening strategies and how they relate to the drug design process.Keywords: Virtual screening; drug design; molecular modeling. ResumoO desenvolvimento de técnicas de triagem virtual representa um dos maiores avanços na atual era de planejamento de fármacos. A triagem virtual, através de inúmeras estratégias distintas, é capaz de direcionar a seleção de moléculas com as características químicas desejadas para modular a atividade biológica dos mais diversos e atrativos alvos moleculares conhecidos na atualidade. Desde as técnicas mais simples, como a bus a po si ila idade ou do age molecular, até as estratégias mais complexas, que envolvem métodos estatísticos e de aprendizagem de máquinas, o objetivo principal da triagem virtual é aprimorar o processo de busca de novos candidatos a fármacos e acelerar o processo contínuo do seu planejamento. O objetivo desta revisão é discutir as principais técnicas de triagem virtual e como elas se relacionam com o desenvolvimento de novos fármacos.Palavras-chave: Triagem virtual; planejamento de fármacos; modelagem molecular.

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Section: Introductionunclassified

Virtual Screening Strategies in Drug Design

Rodrigues¹,

Mantoani²,

Almeida³

et al. 2012

Revista Virtual De Química

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“…[50] However,M organ et al did discover an ew class of covalent inhibitor,w hich targets Leishmania mexicana pyruvate kinase (LmPYK), through ah igh-throughput screen. [50] However,M organ et al did discover an ew class of covalent inhibitor,w hich targets Leishmania mexicana pyruvate kinase (LmPYK), through ah igh-throughput screen.…”

Section: Synthetic Affinity Labelsmentioning

confidence: 99%

“…Using high-throughput screens to discover lysine-targeting irreversible inhibitors is difficult, since reactive small molecules are typically excluded from standard screening collections. [50] However,M organ et al did discover an ew class of covalent inhibitor,w hich targets Leishmania mexicana pyruvate kinase (LmPYK), through ah igh-throughput screen. [51] Analysis of the singleton hit from the screen, and subsequent limited development, led to the thio-linked analogue DBS (17), which demonstrated clear time-dependent inhibition ( Figure 5A,l eft).…”

Section: Synthetic Affinity Labelsmentioning

confidence: 99%

Lysine‐Targeting Covalent Inhibitors

2017

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Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding-site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ϵ-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery.

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“…Die Entdeckung irreversibler, auf Lysin zielender Inhibitoren mittels Hochdurchsatz‐Screening ist schwierig, da reaktive niedermolekulare Verbindungen normalerweise von Screening‐Standardkollektionen ausgenommen sind . Morgan et al.…”

Section: Synthetische Affinitätsmarkierungenunclassified

Auf Lysin zielende, kovalente Inhibitoren

2017

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Zielgerichtete kovalente Inhibitoren haben in der Wirkstoffentwicklung breite Beachtung gefunden, da sie in der Onkologie eine validierte Methode zur Verhinderung erworbener Resistenzen bieten. Dabei werden die Kristallstrukturen der Komplexe von Proteinen mit niedermolekularen Verbindungen verwendet, um fest bindende Liganden mit passend positionierten elektrophilen Gefechtsköpfen (“warheads”) zu entwickeln. Der Schwerpunkt liegt zwar auf Cysteinresten als Bindungsstellen, aber auch nukleophile Lysinreste können einen Zugang zu irreversibler Inhibierung bieten. Allerdings sind mit dieser Methode wegen der Basizität der ϵ‐Aminogruppe in Lysin eine Reihe spezifischer Herausforderungen verbunden. Wir besprechen hier die wichtigen Grundlagen für die Inhibitorplanung, geben historische Beispiele und stellen neue Entwicklungen vor, die das Potenzial von Lysin als Konjugationsstelle in der Wirkstoff‐Forschung belegen.

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Compound Selection and Filtering in Library Design

Cited by 17 publications

References 75 publications

Virtual Screening Strategies in Drug Design

Virtual Screening Strategies in Drug Design

Lysine‐Targeting Covalent Inhibitors

Auf Lysin zielende, kovalente Inhibitoren

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