Building a Bridge between G-Protein-Coupled Receptor Modelling, Protein Crystallography and 3D QSAR Studies for Ligand Design

Abstract

The technique of comparative molecular modelling of protein structures has been known for some time, and there are a large number of guanine nucleotide-binding protein coupled receptor (GPCR) model structures obtained utilizing this technique. Likewise, a growing number of three-dimensional quantitative structure‐activity relationship (3D QSAR) studies have been described on various GPCR ligands using the Comparative Molecular Field Analysis (CoMFA) methodology (see the chapter by Ki Hwan Kim in this volume for a listing). Nonetheless, there are only a few studies that have utilized both techniques for ligand design. Several explanations are possible for this. The most probable reason might be that there are still many uncertainties in the current GPCR models, even though these GPCR models would be refined as the technique improves and additional experimental data become available. A similar statement can be made for the CoMFA methodology, which was invented for the situations where the 3D structure of macromolecule is not known, and this is where it is most frequently used. However, a growing number of CoMFA studies take advantage of the known 3D structure of macromolecule. A third reason for the small number of studies utilizing both techniques might be that many scientists may be an expert on one methodology but not both. As both the GPCR modelling and CoMFA studies progress, examples of the use of both techniques in a study will certainly grow. In some cases, the experts in the field of protein modelling and three-dimensional quantitative structure‐activity (3D QSAR) studies may cooperate to bring the two together. Certainly, more and more scientists will become familiar with both techniques. The objective of this report is to build a bridge between the two techniques: 3D protein modelling and the 3D QSAR approach of CoMFA, toward the common goal of ligand design. Toward this goal, three examples are described below where both CoMFA and a GPCR model were used in a study. Seven more examples are summarized to examine how the protein structures and CoMFA results were used together in other than GPCRs. 2. G-protein Coupled Receptors