Fragment-based lead discovery on G-protein-coupled receptors

Abstract

KEYWORDS GPCR, fragment screening, virtual screening ARTICLE HIGHLIGHTS Recent advances in structural and biophysical characterization of GPCRs lead to improved efficacy of in vitro and in silico fragment-based lead discovery for GPCRs  Virtual fragment screening is a feasible approach for GPCR lead discovery  Multiple receptor conformations (including both experimental and theoretical models) might enhance the success rate of virtual fragment screening  Relevance of biophysical methods for fragment screening and evaluation on GPCRs has increased significantly  In vitro biological assays are suitable for functional screening on GPCRs 2 ABSTRACT Introduction G-protein-coupled receptors form one of the largest groups of potential targets for novel medications. Low druggability of many GPCR targets and inefficient sampling of chemical space in high throughput screening expertise however often hinder discovery of drug discovery leads for GPCRs. Fragment-based drug discovery is an alternative approach to the conventional strategy and has proven its efficiency on several enzyme targets. Based on developments in biophysical screening techniques, receptor stabilization and in vitro assays, virtual and experimental fragment screening and fragment-based lead discovery recently became applicable for GPCR targets.Areas covered Biophysical as well as biological detection techniques suitable to study GPCRs are reviewed, together with their applications to screen fragment libraries and identify fragment-size ligands of cell surface receptors. Several recent examples are presented, including both virtual and experimental protocols for fragment hit discovery and early hit to lead progress. Expert opinionWith the recent progress in biophysical detection techniques the advantages of fragmentbased drug discovery could be exploited for GPCR targets. Structural information on GPCRs will be more abundantly available for early stages of drug discovery projects, providing information on the binding process and efficiently supporting the progression of fragment hit to lead. In silico approaches in combination with biological assays can be used to address structurally challenging GPCRs and confirm biological relevance of interaction early in the drug discovery project.3

What can we learn from molecular dynamics simulations for GPCR drug design?

“…The increasing coverage of the GPCR phylogenetic tree with structural information offers the opportunity to apply structure-based drug design methodologies for this target class [14–17] . One approach which gained increasing attention in pharmaceutical industry over recent years is fragment-based drug discovery [18–20] , which is nowadays reported to be applied also in GPCR drug discovery programs [21–25] . Despite the continuous progress in structure elucidation, the experimental determination of GPCR structures is still a cumbersome and slow process, which does not match the typical cycle times in lead optimization.…”

Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design

“…This study highlights the importance of purely computational FBDD approach for facilitating the design of novel compounds for other targets as well. In addition to the above-mentioned GPCR case studies on SBVFS campaigns, there are several other in silico reports available regarding the discovery of novel ligands which are summarized elsewhere (Hubbard and Murray, 2011 ; Murray et al, 2012 ; Shoichet and Kobilka, 2012 ; Visegrády and Keseru, 2013 ; Andrews et al, 2014 ; Lee et al, 2018 ).…”

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4receptor

“…11,14,15 Biochemical and biophysical fragment screening studies of small chemical libraries (circa 25-1010 compounds) against different GPCRs have been reported with 0.4-14% hit rates yielding several new chemical starting points for fragment-based GPCR ligand optimization. 14,[16][17][18][19][20][21][22] So far only few experimental screens of the same fragment library against multiple GPCR targets have been reported 14,16 that can provide information about the molecular determinants of GPCR-ligand selectivity by fragment-based chemogenomics analyses. 14,23 Virtual fragment screening approaches, the in silico prediction of fragment binding to protein binding sites that has the potential to explore protein-ligand space more extensively, have been successfully applied to identify new fragment-like ligands for several GPCR targets, with 20-73% hit rates (% of experimentally tested in silico hits with detectable binding affinity).…”

“…14,23 Virtual fragment screening approaches, the in silico prediction of fragment binding to protein binding sites that has the potential to explore protein-ligand space more extensively, have been successfully applied to identify new fragment-like ligands for several GPCR targets, with 20-73% hit rates (% of experimentally tested in silico hits with detectable binding affinity). 18,20,22,[24][25][26][27] While ligand-based virtual screening methods often only allow the identification of chemically similar ligands, protein-based virtual screening approaches potentially offer the possibility of scaffold hopping, the discovery of ligands with new chemical functional groups. 24,[28][29][30] GPCR structure-based virtual fragment screening (SBVFS), 18,22,[24][25][26] the identification of smaller fragmentlike molecules by docking simulations 31 of large chemical databases in GPCR 3D structures, is however, still challenging and several problems have been identified including: (i) Conformational sampling problem: proper consideration of protein flexibility in docking simulations is difficult and small differences between experimentally-determined crystal structures, as well as structural inaccuracies in protein homology models, can affect sampling and scoring of different GPCRligand conformations.…”

“…18,20,22,[24][25][26][27] While ligand-based virtual screening methods often only allow the identification of chemically similar ligands, protein-based virtual screening approaches potentially offer the possibility of scaffold hopping, the discovery of ligands with new chemical functional groups. 24,[28][29][30] GPCR structure-based virtual fragment screening (SBVFS), 18,22,[24][25][26] the identification of smaller fragmentlike molecules by docking simulations 31 of large chemical databases in GPCR 3D structures, is however, still challenging and several problems have been identified including: (i) Conformational sampling problem: proper consideration of protein flexibility in docking simulations is difficult and small differences between experimentally-determined crystal structures, as well as structural inaccuracies in protein homology models, can affect sampling and scoring of different GPCRligand conformations. [32][33][34][35] In particular, docking small fragments in a large binding pocket may result in multiple distinct binding modes with similar docking scores.…”