RESUMO
Nucleosides and nucleotides which are able to undergo covalent hydration in the aglycone ring system are potential inhibitors of the enzymes adenosine deaminase (ADA) and AMP deaminase, respectively. Calculations of the enthalpy of covalent hydration and of enzyme binding energy have been used to design new inhibitors of ADA. The ribosyl triazolotriazine 16, which was synthesized as a result of these calculations, exists predominantly as the covalent hydrate 18 in water and is a potent inhibitor of mammalian ADA (IC(50) 50 nM).
Assuntos
AMP Desaminase/antagonistas & inibidores , Inibidores de Adenosina Desaminase , Inibidores Enzimáticos/química , Nucleosídeos/química , Nucleotídeos/química , Animais , Calorimetria , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Mamíferos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Nucleotídeos/síntese química , Nucleotídeos/farmacologia , TermodinâmicaRESUMO
Computer-based assessment of potential toxicity has become increasingly popular in recent years. The knowledge-base system DEREK is developed under the guidance of a multinational Collaborative Group of expert toxicologists and provides a qualitative approach to toxicity prediction. Major developments of the DEREK program and knowledge-base have taken place in the last 3 years. Program developments include improvements in both the user interface and data processing. Work on the knowledge-base has concentrated on the areas of genotoxicity and skin sensitisation. DEREK's predictive capabilities for these toxicological end-points has been demonstrated. In addition to the continued expansion of the knowledge-base, a number of enhancements are planned in the DEREK program. In particular, work is in progress to develop further DEREK's ability to report the reasoning behind its predictions.
Assuntos
Carcinógenos , Simulação por Computador , Sistemas Inteligentes , Substâncias Perigosas/toxicidade , Software , Toxicologia/métodos , Alternativas aos Testes com Animais , Interpretação Estatística de Dados , Bases de Dados Factuais , Dermatite Alérgica de Contato , Humanos , Mutagênicos , Reprodutibilidade dos Testes , Pele/efeitos dos fármacos , Relação Estrutura-Atividade , Interface Usuário-ComputadorRESUMO
1. The development of DEREK, a computer-based expert system (derived from the LHASA chemical synthesis design program) for the qualitative prediction of possible toxic action of compounds on the basis of their chemical structure is described. 2. The system is able to perceive chemical sub-structures within molecules and relate these to a rulebase linking the sub-structures with likely types of toxicity. 3. Structures can be drawn in directly at a computer graphics terminal or retrieved automatically from a suitable in-house database. 4. The system is intended to aid the selection of compounds based on toxicological considerations, or separately to indicate specific toxicological properties to be tested for early in the evaluation of a compound, so saving time, money and some laboratory animals and resources.
Assuntos
Sistemas Computacionais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Toxicologia/métodos , Animais , Carcinógenos , Gráficos por Computador , Humanos , Relação Estrutura-AtividadeRESUMO
Carbocylic coformycin (4) is a potent herbicide whose primary mode of action involves inhibition of adenosine 5'-monophosphate deaminase (AMPDA) following phosphorylation of the 5'-hydroxyl group in vivo. The search for more stable and accessible structures led to the synthesis of carbocyclic nebularine (8) and deaminoformycin (10). The latter compound is a good herbicide and its corresponding 5'-monophosphate 14 is a strong inhibitor of plant AMPDA (IC50 100 nM).