A Novel Chemogenomics Knowledge-Based Ligand Design Strategy—Application to G Protein-Coupled Receptors

Abstract

In the frame of the discussion of monoamine-related GPCRs, a novel knowledge-based ligand design strategy is presented. The strategy is founded on the integration of both, the deconvolution of known ligands into their component fragments and the structural bioinformatics comparison of the binding sites for the individual ligand fragments. Positioning analyses of monoamine-related GPCRs in 1) the sequence space of the seven transmembrane domains of the receptors, and 2) in the sequence spaces of the previously identified three distinct ligand fragment binding regions of the monoamine GPCRs, are carried out in the perspective to characterize orphan receptors and monoamine receptors for which no specific ligands are yet known. Compared to the commonly accepted strategy to analyze the overall sequence identity of the seven transmembrane domains in order to find starting points for lead finding and ligand design programs, the strategy to localize the sequence homology to the different ligand fragment binding sites clearly enhances the identification of putative similarities for the orphan receptors. Correspondingly, in the ligand space, by the analysis of both, the ligand architectures and the structures of the component ''one-site filling'' fragments of known GPCR ligands, it is then possible, by referring to the locally most directly related and characterized receptors, to identify those component ligand fragments which based on the binding site similarities are potentially best suited for the design of ligands tailored to the new target receptor. Predictions are made for several orphan GPCRs, including GPR7, GPR8, GPR14, GPR24, GPR57, GPR58 and AF021818, as well as for the 5HT 1E and 5HT 5 serotonin receptors for which no specific agonists and antagonists are yet known. Although the method is herein discussed with a focus on GPCRs, it is expected that such chemogenomics knowledge-based strategies -bridging the chem-and bioinformatics worlds -should open novel perspectives in drug discovery for orphan targets revealed by the human genome project belonging to other therapeutic target families.

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

“…They described the aligned 7TM helices of the aminergic GPCRs by physicochemical descriptors and applied a multivariate analysis to explore the interactions of the TM helix amino acids of the R 1a -, R 1b -, and R 1d -adrenoreceptors with 4-piperidyl oxazole antagonists. Jacoby 70 reports that the monoamine-related GPCR sequences can be unambiguously identified by the presence of the TX(DE)R(IF) motif in the TM3 helix (note that this motif is not involved in the LPVs introduced here). Furthermore, for aminergic GPCRs, he compares the results of the standard phylogenetic analysis of the 7TM domain to phylogenetic relationships derived from amino acid fingerprints identified by mutational analysis for three different 5HT1A receptor ligands.…”

Structure prediction and binding sites analysis of curcin protein of Jatropha curcas using computational approaches

“…The conservation of the sequence encoding the binding site within a target family leads putatively also to conservation of the shape and physicochemical properties of the ligand binding sites, resulting in a similarity of the structural requirements for ligands [64]. Among the ten residues in the adenine binding site seven were exactly the same in the structure of both the RIP family members.…”

“…Structure-based inhibitor design has become increasingly important in the rational process of discovery of new analog and inhibitor compounds. The molecules similar to molecules of a reference set formed by ligands of a previously investigated target can be expected to have some activity also on other targets within the same family [64]. Because of significant structural similarity it is expected that ricin inhibitors may inhibit curcin and both the proteins can be thought of as SAR homologs.…”

Medicinal Chemistry in the Context of the Human Genome

“…Using information from databases of protein structures, ligand-based, sequencebased, and structure-based methods of identifying leads have been introduced based on a paradigm of "similar receptors bind similar ligands" [63][64][65][66][67]. These techniques are particularly attractive when the structure of a target is not known, as is usual for members of the GPCR family.…”