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The Drug Discovery Unit (DDU) (est. 2006) within the College of Life Sciences at Dundee was created to respond to a lack of capacity in the UK for early stage drug discovery in the academic sector. The DDU’s aim is to translate basic science into lead compounds to validate putative drug targets, to use as tools to investigate disease pathways and, when appropriate, advance to pre-clinical drug candidates for multiple diseases, e.g. visceral leishmaniasis or malaria. The DDU works to Biotech style philosophy and standards incorporating dynamic, goal driven project management based on Target Product Profiles and Compound Selection Criteria. The DDU is a fully operational and integrated drug discovery team, which is rare within UK universities, with the full range of disciplines, including compound management, screening, molecular pharmacology/enzymology, medicinal chemistry, computational chemistry, DMPK and disease model capabilities, required to produce novel hit and lead candidates.
Our funding for early drug discovery up to drug candidate nomination comes from a number of sources. Of particular note, we are funded by Wellcome to deliver drug candidates for kinetoplastid diseases (Chagas’ disease as current priority) in collaboration with GlaxoSmithKline’s Kinetoplastid Diseases DPU, Tres Cantos, Spain. In addition, we are funded by the medicines for malaria venture (MMV) to discover drug candidates for malaria; and we are funded by the Bill and Melinda Gates Foundation to discover leads and deliver preclinical development candidates for tuberculosis (TB).
My background is in drug metabolism and pharmacokinetics (DMPK), with extensive experience of early phase drug discovery, lead optimisation project leadership and preclinical development gained from over 32 years in the pharmaceutical industry. My passion is to successfully drive lead optimisation forward, working closely with the medicinal chemists to deliver high quality candidate molecules for entry into formal preclinical development. Since moving to the DDU at the University of Dundee in 2008, I have built a DMPK department from the ground up. I currently have 20 DMPK scientists with all the skills and tools necessary to ensure that only those molecules with appropriate developability to deliver the required target product profile will progress through lead optimisation.
A robust preclinical development candidate will have a balance of good potency, safety and DMPK properties. These compound characteristics should therefore be optimised as early as possible in the drug discovery process so that cycle times and progression to humans is as uneventful as possible.
My group has implemented industry standard assays coupled with state of the art UPLCMSMS technology for supporting all hit to lead and lead optimisation programmes within the DDU. Our capabilities include in silico absorption, distribution, metabolism and excretion (ADME) models, together with a range of in vitro and in vivo tools, selected in order to provide a good overall assessment of the developability profile of compounds early in the optimisation process.
Our available in vitro assays include assessment of measured physicochemical properties such as pKa and LogP; assessment of metabolic stability (intrinsic clearance) using liver microsomes, hepatocytes or cytosol from a range of preclinical species and human; assessment of drug-drug interaction and bioactivation risk using recombinant enzymes or human liver microsomes, evaluating CYP450 inhibition, metabolism dependent inhibition, glutathione trapping and performing reaction phenotyping to give a preliminary understanding of the enzymology involved in the metabolism of a new compound; aqueous and biorelevant media solubility; determination of compound stability in different matrices (blood, SGF, buffer etc); and plasma protein and tissue binding determination using equilibrium dialysis in a 96-well format. Assessing plasma protein and tissue binding allows for correction to the free plasma and free tissue concentration, both of which may be more meaningful indicators of the true efficacious concentration of a compound and so aid in understanding of pharmacokinetic/pharmacodynamic (PK/PD) relationships and, through calculation of theoretical receptor occupancy, enable better initial design of pharmacodynamic experiments.
Together with these in vitro assays, my group, on a routine basis, performs in vivo pharmacokinetics (PK), and brain penetration studies in rodents, usually mice. My in vivo pharmacologists have the expertise to perform serial blood sampling in mice so that a full PK profile can be obtained from a single animal thus significantly reducing animal usage. Additionally the in vivo pharmacologists can perform in vivo assessment of Pgp interaction using mdr1a deficient mice or chemical knockout; hepatic portal vein sampling in rats in order to obtain information on fraction absorbed and hepatic extraction that can aid in more rapidly identifying the key issues for poor bioavailability; and can provide PK/PD support using oral and/or a number of parenteral dose routes (i.v., s.c., i.p., i.m) as required to determine drug exposure in order to ensure optimal PD study design and build a better understanding of the PK/PD relationship within projects.
Our capability to perform metabolite identification from in vitro incubates or from biological matrices obtained following in vivo PK experiments has been enhanced through purchase of a UPLC Xevo Qtof MSMS and a Thermo Exploris 120. This helps guide medicinal chemistry and can provide early indications of toxicity.
My group is also responsible for running the animal efficacy studies in support of all our kinetoplastid disease programmes. This allows a more nimble progression through to in vivo efficacy if a compound is identified as having appropriate pharmacokinetics to deliver efficacy at a well tolerated dose. Furthermore, with the need to rapidly validate targets in vivo, we use, when viable, CYP450 chemical knockout, HRNTM (CYP450 hepatic null) mice, 8HUM humanised mice and/or implanted osmotic pumps in efficacy studies on those targets with poorly optimized chemistry in order to achieve and maintain prolonged efficacious free concentration of a compound in a mouse without the need for compound optimisation apriori.
Review of the Year 2021 took place virtually today with the former Interim Dean, Inke Näthke sharing the highlights of activity within the School from 2021
Experts at the University of Dundee have been awarded £2.4 million to identify compounds that could pave the way for a single dose treatment for malaria.
Researchers from the Drug Discovery Unit at the University of Dundee have been awarded the “Project of the Year 2018” from Medicines for Malaria Venture (MMV) for their discovery work on potential new drugs for malaria
Drug discovery, lead optimisation and preclinical development