Structural Chemoinformatics Tools for GPCR Structure-Based Drug Design
Chris de Graaf1, Rob Smith1, Conor Scully1, Francesca Deflorian1, Juan Carlos Mobarec1, Ben Tehan1, Jon Mason1, Miles Congreve1
1Sosei Heptares
Novel crystal structures of GPCR-ligand complexes solved at Heptares and elsewhere continue to reveal a diversity of potential ligand binding sites, such as new allosteric binding sites for Class A and Class B GPCRs [1]. Emerging sets of GPCR crystal structures of multiple diverse ligands bound to closely related receptors furthermore finally enable a protein-structure based view of how different ligands bind this major drug target class.
This presentation will address several important repercussions and learnings from the analysis of GPCR structures for ligand design that should be transferable and relevant for many targets, both GPCRs and enzymes, including:
– Caveats in using pharmacophore based similarity principles for modeling receptor ligand complexes different ligand chemotypes
– The important roles of lipophilic hot spots and water networks as drivers of GPCR druggability, ligand binding, and selectivity
– Binding mode diversity of (chemically similar) ligands across the structural GPCRome
This presentation will show how the breakthroughs in GPCR structural biology can be complemented by computational and experimental studies for a more accurate description and prediction of molecular and structural determinants of ligand-receptor binding affinity, kinetics, potency, and selectivity. Integrated cheminformatics workflows will be described that combine structural, pharmacological, and chemical data to explore receptor-ligand interaction space [2] and steer structure-based virtual ligand screening [3].
The presentation will provide examples how the accumulated GPCR structural chemogenomics data can be used to construct customized structure-based medicinal chemistry toolboxes for hit optimisation and library design. Orthogonal physics-based (Molecular Dynamics, e.g. Free Energy Perturbation FEP+, WaterMap from Schrödinger) and empirical (e.g. GRID and WaterFLAP from Molecular Discovery) structure-based drug design methods will be presented to target lipophilic hotspots, water networks [4], and cryptic ligand binding pockets for a variety of GPCR subfamilies.
References:
[1] Congreve, Oswald, Marshall (2017) Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. Tr Pharmacol Sciences 38, 837. doi: 10.1016/j.tips.2017.05.010.
