One of the most challenging issues for the future of drug discovery is the capability to understand the GPCR–ligand recognition pathway with the aim to facilitate the development of drug candidates with more favorable phamacodynamic profiles. Unfortunately, the recognition process between a ligand and its receptor is a very rare event to describe at the molecular level, and even with the recent GPU-based computing resources, it is necessary to carry out classical molecular dynamics (MD) experiments in a long microsecond time scale. In order to overcome this limiting factor, we have implemented an alternative MD approach, named supervised molecular dynamics (SuMD), that enables us to follow GPCR–ligand approaching process within a time scale reduced up to three orders of magnitude compared to classical MD [1]. SuMD enables the investigation of ligand–receptor binding events independently from the starting position, chemical structure of the ligand, and also from its receptor binding affinity (Fig. 1). We selected as a key study the human A2A adenosine receptor (hA2AAR) that has been recently crystallized with different ligands, both agonists and antagonists, characterized by different receptor binding affinities. We are able to accurately completely explore the receptor–ligand event in a nanosecond time scale. This approach is also very useful to analyze both orthosteric and allosteric binding events broadening our perspectives in several scientific areas from molecular pharmacology to drug discovery.
Inspecting receptor-ligand interaction using molecular dynamics simulations: new insights from Adenosiland
Ciancetta AUltimo
2014
Abstract
One of the most challenging issues for the future of drug discovery is the capability to understand the GPCR–ligand recognition pathway with the aim to facilitate the development of drug candidates with more favorable phamacodynamic profiles. Unfortunately, the recognition process between a ligand and its receptor is a very rare event to describe at the molecular level, and even with the recent GPU-based computing resources, it is necessary to carry out classical molecular dynamics (MD) experiments in a long microsecond time scale. In order to overcome this limiting factor, we have implemented an alternative MD approach, named supervised molecular dynamics (SuMD), that enables us to follow GPCR–ligand approaching process within a time scale reduced up to three orders of magnitude compared to classical MD [1]. SuMD enables the investigation of ligand–receptor binding events independently from the starting position, chemical structure of the ligand, and also from its receptor binding affinity (Fig. 1). We selected as a key study the human A2A adenosine receptor (hA2AAR) that has been recently crystallized with different ligands, both agonists and antagonists, characterized by different receptor binding affinities. We are able to accurately completely explore the receptor–ligand event in a nanosecond time scale. This approach is also very useful to analyze both orthosteric and allosteric binding events broadening our perspectives in several scientific areas from molecular pharmacology to drug discovery.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
