Strategies for the generation, validation and application of in silico ADMET models in lead generation and optimization.
Expert Opin Drug Metab Toxicol
; 8(11): 1435-46, 2012 Nov.
Article
em En
| MEDLINE
| ID: mdl-22849616
ABSTRACT
INTRODUCTION:
The most desirable chemical starting point in drug discovery is a hit or lead with a good overall profile, and where there may be issues; a clear SAR strategy should be identifiable to minimize the issue. Filtering based on drug-likeness concepts are a first step, but more accurate theoretical methods are needed to i) estimate the biological profile of molecule in question and ii) based on the underlying structure-activity relationships used by the model, estimate whether it is likely that the molecule in question can be altered to remove these liabilities. AREAS COVERED In this paper, the authors discuss the generation of ADMET models and their practical use in decision making. They discuss the issues surrounding data collation, experimental errors, the model assessment and validation steps, as well as the different types of descriptors and statistical models that can be used. This is followed by a discussion on how the model accuracy will dictate when and where it can be used in the drug discovery process. The authors also discuss how models can be developed to more effectively enable multiple parameter optimization. EXPERT OPINION Models can be applied in lead generation and lead optimization steps to i) rank order a collection of hits, ii) prioritize the experimental assays needed for different hit series, iii) assess the likelihood of resolving a problem that might be present in a particular series in lead optimization and iv) screen a virtual library based on a hit or lead series to assess the impact of diverse structural changes on the predicted properties.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
/
Desenho de Fármacos
/
Descoberta de Drogas
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Expert Opin Drug Metab Toxicol
Assunto da revista:
METABOLISMO
/
TOXICOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Tailândia