RESUMO
We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the ß-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCRs other than the intended target, which could be partly attributed to the fuzziness and overlap of protein-based pharmacophore models. Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil was found to possess submicromolar affinity for AA2AR. Overall, this is one of the first published prospective chemogenomics studies that demonstrate the identification of novel cross-pharmacology between unrelated protein targets. The lessons learned from this study can be used to guide future virtual ligand design efforts.
Assuntos
Bases de Dados Factuais , Desenho de Fármacos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Receptores A2 de Adenosina/química , Receptores Adrenérgicos beta 2/química , Receptores de Lisoesfingolipídeo/química , Agonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/química , Agonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/química , Animais , Células CHO , Cricetinae , Cricetulus , Agonismo Parcial de Drogas , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Estrutura Molecular , Inibidores da Fosfodiesterase 5/química , Piperazinas/química , Piperazinas/metabolismo , Purinas/química , Purinas/metabolismo , Ensaio Radioligante , Receptores A2 de Adenosina/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/metabolismo , Citrato de Sildenafila , Processos Estocásticos , Sulfonas/química , Sulfonas/metabolismoRESUMO
The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.