Impact case study database

The CATH classification, made available on a UCL-hosted website maintained by the Orengo group, is an internationally renowned resource and one of the world’s leading protein structure classifications in this field [S1]. There are more than 22,500 unique web visits to CATH per month and 2,000,000 pages are accessed per month [S1]. Two-thirds of these web visits are from industry-based sites [S1]. CATH has been made an ELIXIR Europe-wide Core Data Resource (CDR) [S2], one of only three European national resources to be endorsed as meeting the highest standards in data quality and data access established by the ELIXIR (European Strategy Forum on Research and Innovation), - excellent science, community served, high quality of service and impact - and, notably, the only CDR to be endorsed in the UK . [TEXT REMOVED FOR PUBLICATION].

CATH data is further disseminated through the InterPro web server, at the European Bioinformatics Institute (EBI). Outside academia, InterPro is one of the most widely used web portals by biologists in industry, with over 723,000 unique visitors per year. It combines protein family data from multiple resources to assign greater confidence. CATH data is also disseminated via the web portal of the international protein structure resource, the Protein Databank (PDB), with over 4,411,871 unique users/year, and UniProt, a major source of protein functional data with over 10,800,000 unique users/year (2,220,00 of which are from industry). Further links to CATH are provided by many international web-based computational biology resources, for example Pfam, BRENDA [S1]).

CATH was one of four major resources used to establish the UCL spinout company Inpharmatica. It was also used by Inpharmatica to provide data and services for predicting protein structures and functions for large pharmaceutical companies including Pfizer, AstraZeneca, Merck and Glaxo-Wellcome [S3]. [TEXT REMOVED FOR PUBLICATION] Inpharmatica has since been acquired by biotechnology company Galapagos. Since 2013, Galapagos has attracted over GBP11,000,000 in investment [S4].

The structure comparison algorithms underpinning CATH (CATHEDRAL) have been distributed directly to pharmaceutical companies, including UCB Celltech and Cubist Pharmaceuticals, generating GBP34,931 in licence income to UCL within the census period [S5]. Papers published by Orengo have been cited across eight patent documents, demonstrating the commercial relevance of the work.

Users in industry exploit the CATH prediction methods, domain assignments and methods (e.g. CATHEDRAL) for analysing their structures. For example, R&D staff in DSM Chemical Technology R&D BV used CATHEDRAL to search CATH for structural homologues of a protein they were solving; a biocatalyst valuable for the pharmaceutical industry because of its ability to synthesis various beta-hydroxy amino acids - compounds widely used in food processing and drug development [S6].

Specific applications to problems in the pharmaceutical industry

Identifying disease drug targets: CATH is routinely used by the pharmaceutical industry to identify the structures of proteins implicated in disease. Predicted functional site data is used to assess the effects of disease-associated residue mutations and to identify putative ligand (i.e. drug) binding sites and variation in drug-binding modes across families. CATH has been used, for example, by:

• Gene Tools LL and BrainMicro LLC, to identify domain boundaries in enzymes being structurally characterised as potential therapeutic targets for toxoplasmosis and other parasitic infections [S7];

• Phylogica Ltd to search fold space in the characterisation of a peptide library used for target discovery, and for identifying new cell-penetrating peptides [S8];

• Acpharis, to identify the domains of kinases - a major drug target family for pharmaceutical companies [S9]; and

• AstraZeneca, for structural analyses that identified pharmacophore binding motifs for NAD (Nicotinamide adenine dinucleotide– an critical component in metabolism) and its analogues across different protein families [S10].

Biologic drug design: CATH data is also being used for biologics in large pharma companies. [TEXT REMOVED FOR PUBLICATION].

Pathogen protein structure-based drug design: CATH FunFam technology was exploited by NIH-funded, international, structural genomics initiatives (between 2013 and 2017) to select proteins from pathogenic organisms for structure determination to aid drug design. More than 2,400 protein structures were deposited into the Protein Databank from all sources, worldwide, during this period. These structures have shed light on how structure is linked to function and provided important details of binding sites in proteins implicated in cancer and pathogen associated diseases.

Covid-19: More recently, CATH FunFam analyses of binding sites involved in SARS-CoV-2 infection of animal hosts was used by the WHO and a UN Food and Agriculture Organisation policy unit [S11] in strategy discussions on animals at risk from infection, or which are likely to become reservoirs for the virus. These sites constitute major mechanisms of infection which are targetable by drugs. The work was also reported in several newspapers globally.

Orengo has given talks on CATH in Europe, the United States, Singapore, China, Malaysia, Africa and India, including the EBI Industry program and to computational biologists at several pharmaceutical companies.