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Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists.
J Chem Inf Model ; 59(9): 3996-4006, 2019 09 23.
Article em En | MEDLINE | ID: mdl-31433190
ABSTRACT
Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal, and metabolic abnormalities, while avoiding the psychoactive effects in the central nervous system. We applied our in-house algorithm, iterative stochastic elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules by physicochemical properties only. We screened ∼2 million commercially available molecules and found that about 500 of them are potential candidates to antagonize the CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to the CB1R and two of them with nanomolar affinities (Ki of ∼400 nM). The eight molecules with top affinities were tested for activity two compounds were pure antagonists, and five others were inverse agonists. These molecules are now being examined in vivo for their peripheral versus central distribution and subsequently will be tested for their effects on obesity in small animals.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Biologia Computacional / Receptor CB1 de Canabinoide / Bibliotecas de Moléculas Pequenas / Aprendizado de Máquina Tipo de estudo: Prognostic_studies / Risk_factors_studies Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Biologia Computacional / Receptor CB1 de Canabinoide / Bibliotecas de Moléculas Pequenas / Aprendizado de Máquina Tipo de estudo: Prognostic_studies / Risk_factors_studies Idioma: En Ano de publicação: 2019 Tipo de documento: Article