NQuiX has been closely involved in the National Compound Collection pilot study – an evaluation of the chemical diversity represented in a sampling of chemistry PhD theses submitted in the UK and its potential for application in pharmaceutical research.
In work with the Royal Society of Chemistry and Bristol University, a team of data extractors created the National Compound Collection (NCC) database of ~75,000 chemical structures from over 700 theses. NQuiX developed computational methods for assessing the chemical diversity of the NCC in terms of fingerprint similarity, Bemis-Murcko frameworks and ring systems after substructural and property filtering for druglikeness. The approach was encoded in a script to facilitate standardized comparison to a wide range of compound collections including known drugs, published bioactive compounds, patented chemistry space, “purchaseable” compounds and various screening decks. For the latter, the script was run by 12 external drug discovery groups from pharma, biotech, academic and not-for-profit sectors. The output was combined to provide a broad view of the potential value of the novel chemical diversity present.
The results of the pilot study have been published in Chemical Science (DOI: 10.1039/C6SC00264A). Whilst the proportion of structures passing the various filters and appearing to be novel varies quite widely depending on stringency and compound collection, a subset of ~13k structures (~18% of the NCC) look to have good diversity. This seems like a very encouraging proportion and helps to frame thinking in terms of capturing additional value in UK academic chemistry research output.
The NCC database and scripts for comparison are available as part of the supplementary material. The NCC database has also been uploaded to ChemSpider to provide additional access and searching options.
The paper “Are GPCRs Still a Source of New Targets?” written by Stephen Garland has won the 2016 JBS Authors Choice Award reflecting its popularity among authors (citations) throughout 2015. The paper is open access and can be readily downloaded from the JBS website.
The article discusses the wide range of opportunities that remain for discovery of new drugs at arguably the most successful class of drug targets to date, including under-exploited receptor sub-classes, new chemical diversity, advances in understanding of receptor pharmacology, screening technology and protein X-ray crystallography, as well as the scope for allosteric mechanisms, alternative signalling pathways, the discovery of “biased” ligands and the emergence of GPCR-protein complexes as potential drug targets.
A screening library of >8,000 compounds has been designed in collaboration with Enamine based on available and newly synthesized compounds. These target the family of 8 EDG receptors (S1P1-5 and LPA1-3). The compounds may also be appropriate for screening at GPR3, GPR6 and GPR12 orphan receptors given some TM bundle binding site similarity and/or GPR23, GPR92 and P2Y5 given their more recent classification as additional, albeit distinct, LPA receptors. Compounds targeting the receptors have potential application in inflammation, immune disease, cancer, CNS diseases as well as other indications. The compounds have been selected using a combination of ligand-based methods including chemical fingerprints, 2D pharmacophores and 3D shape/feature matches. They represent a combination of compounds for expanding SAR around known chemotypes and scaffold hops seeking novelty. The current set of compounds covers the non-acidic classes of ligand, with acidic compounds being designed via a different procedure and offered separately.
What is the potential of G-Protein Coupled Receptor allosteric sites in drug design?
In an editorial published in Future Medicinal Chemistry, Stephen Garland discusses the progress being made with the identification and exploitation of allosteric binding sites at G-Protein Coupled Receptors, their potential to open up targets that have otherwise proven intractable and to identify compounds with new and improved efficacy.
At least 5 allosteric sites appear to be available at GPCRs:
1. Within the TM bundle at a site distinct from that used by the endogenous ligand;
2. Within the extracellular loops in an “ectopic” site;
3. On (rather than within) the extracellular loops;
4. At an intracellular site;
5. In one of possibly several membrane-facing sites.
The various sites have differences in terms of their properties and hence potential as targets for drug design.
The publication is available from http://www.future-science.com/doi/full/10.4155/fmc.14.32 or via doi:10.4155/fmc.14.32.
The article “Are GPCRs Still a Source of Drug Targets?” by Stephen Garland has been published in the Journal of Biomolecular Screening.
G-protein–coupled receptors (GPCRs) still offer enormous scope for new therapeutic targets. Currently marketed agents are dominated by those with activity at aminergic receptors and yet they account for only ~10% of the family. Progress up until now with other subfamilies, notably orphans, Family A/peptide, Family A/lipid, Family B, Family C, and Family F, has been, at best, patchy. This may be attributable to the heterogeneous nature of GPCRs, their endogenous ligands, and consequently their binding sites. Our appreciation of receptor similarity has arguably been too simplistic, and screening collections have not necessarily been well suited to identifying leads in new areas. Despite the relative shortage of high-quality tool molecules in a number of cases, there is an emerging, and increasingly substantial, body of evidence associating many as yet “undrugged” receptors with a very wide range of diseases. Significant advances in our understanding of receptor pharmacology and technical advances in screening, protein X-ray crystallography, and ligand design methods are paving the way for new successes in the area. Exploitation of allosteric mechanisms; alternative signaling pathways such as G12/13, Gβγ, and β-arrestin; the discovery of “biased” ligands; and the emergence of GPCR-protein complexes as potential drug targets offer scope for new and much improved drugs.
To access the paper, visit: http://jbx.sagepub.com/content/18/9/947 or use DOI 10.1177/1087057113498418.