Our structural understanding of the superfamily of G-protein coupled receptors, a group of targets of utmost pharmacological
importance, has improved dramatically in the last few years. This was directly translated in an increase of both the number and the relevance
of computer-assisted drug design efforts devoted to these receptors. The field, which had been greatly influenced by ligand-based
methods, has experienced a radical transformation with a number of successful structure-based ligand design and ligand discovery studies.
This revolution has been accompanied by the exponential increase of computational resources, and as a result the scenario in GPCR
structural and chemical studies is now more complex and richer than ever. Virtual screens, both structure- and ligand-based, co-exist with
accurate computational characterizations of the receptor conformational dynamics and of the energy landscapes of receptor-ligand interactions.
We here provide an integrated and updated view of the different computational techniques applied to the ligand design of
GPCRs. Particular emphasis is put on the studies that take into account the novel structural information of GPCRs, together with those
that consider the enormous amount of chemical information accumulated on these receptors in the last decades. Indeed, we propose that
proper combinations of the different computational techniques: ligand-based, structure-based and molecular dynamics studies, should be
performed to better integrate all available information whenever possible. With this in mind, a major impact of computational technologies
in the ligand design on GPCRs is expected in the forthcoming years.
Keywords: Docking, free energy calculations, GPCR, MD simulations, modeling, QSAR, virtual screening, computer-assisted drug design, radical transformation, chemical information
Rights & PermissionsPrintExport