LeadBuilder is an innovative technology which enables entrepreneurs and academics to take their disease targets through the first phase of drug discovery. All the acquired information enables these groups to take their conceptual ideas and apply for further translational research grants – such as with the Wellcome Trust Seeding Drug Discovery Initiative and the MRC Developmental Pathway Funding Scheme.
The technology integrates Domainex’s state-of-the-art capability in three key areas: compound collection design and selection; protein modelling and virtual screening. LeadBuilder encapsulates many aspects of Domainex’s scientists’ expertise in successful drug-hunting.
The principles of LeadBuilder are that there is a large number (over 12 million) of compounds that exist and, at least in theory, represent starting points for drug discovery. The challenge to the scientist is that many of these compounds are not actually available to purchase or, just as important, have physical or chemical properties that make them undesirable starting points for drug discovery. Domainex’s approach is to triage the known compounds to provide an optimised set of starting points.
Within LeadBuilder, there is a database (“NICE”) of 250,000 commercially-available compounds that have been carefully selected to meet all criteria for an “ideal” screening hit. For example, the NICE database of compounds is unique in that the compounds have been selected to have several potential points of interaction with a target protein, which will increase the likelihood of finding an inhibitor or a target. The NICE library is also filtered to ensure that compounds have excellent physiochemical. Moreover, the compound collection contains compounds selected to have good predicted ADME-Tox profiles.
The NICE compounds are then applied to protein drug targets using target and ligand structures obtained from X-ray crystallography, or alternatively, should such information not be available, using in silico models based upon active-site similarity. From these data, a model of the active site of a target can be obtained for virtual screening and design purposes. The final step in LeadBuilder is an individual review of the compounds suggested by LeadBuilder from Domainex’s team of highly experienced medicinal and computational chemists to ensure that these suggestions are of the highest quality.
LeadBuilder can interrogate databases of commercially-available compounds with target-specific queries. defined by using protein and/or ligand derived information. The latest enhancements to LeadBuilder include an expanded database of over six million commercial compounds, and the incorporation of a number of software upgrades. Compounds which Domainex selects using LeadBuilder are purchased and tested in biochemical assays to give hit rates which are typically between 1-10%: i.e. three orders of magnitude better than generally obtained from random, high-throughput screening (HTS). Critically, in contrast to HTS, hits from LeadBuilder are high quality, as they are rich in pharmacophoric features and possess highly favourable molecular, ADME and toxicity profiles.
Dr Trevor Perrior, Research Director of Domainex, commented: “It is generally agreed that one of the most influential factors in determining whether or not a drug research project will be successful is the quality of the starting point, which is usually a screening hit. By using LeadBuilder, we can make high-quality hits available to everyone without them needing to make an investment in the time and expense of high-throughput screening. The latest generation LeadBuilder has been successfully validated on several targets - both for clients such as Breakthrough Breast Cancer, and for Domainex’s internal pipeline - and we look forward to working with this powerful technology on our customers’ drug discovery projects”.