title: A new paradigm for navigating compound property related drug attrition.
abstract: Improving the efficiency of drug discovery remains a major focus for the pharmaceutical industry. Toxicity accounts for 90% of withdrawals and major early-stage terminations relate to suboptimal efficacy and safety. Traditional oral drug space is well defined with respect to physicochemical properties and ADMET risks but increased focus on ligand-lipophilicity efficiency, maximizing enthalpy contributions and new target classes challenge this paradigm. A hybrid space has been identified that combines physical properties and key interactions attributable to drug transporters. A novel algorithm is proposed that incorporates drug-transporter interactions and its utility evaluated against popular ligand efficiency indices. Simply reducing the bulk properties of compounds can exchange one problem for another and creates high-risk areas that challenge the successful delivery from a balanced portfolio.
authors.affiliation: School of life Sciences, University of Nottingham, Nottingham, UK. Electronic address: patrick.barton@nottingham.ac.uk.
authors.forename: Patrick
authors.initials: P
authors.lastname: Barton
authors.affiliation: Evotec UK, Abingdon, Oxfordshire, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Riley
mesh_terms: D001692:Biological Transport / Q000502:physiology; D055808:Drug Discovery / Q000379:methods; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations