Málstofa í efnafræði og lífefnafræði,
Benchmarking in Drug Discovery.
Jóhannes Reynisson, PhD in chemistry, Department of Chemistry and Auckland Bioengineering Institute, The University of Auckland, New Zealand.
Fyrirlestur föstudag 26. febrúar kl 12.30 í stofu 158 í VR II.
Abstract: The concept of ‘known drug space’ is applied in three different scenarios in pre-clinical drug development as a benchmarking tool. The rationale behind ‘known drug space’ is simple: only marketed drugs that are actually administered to millions of people every day are used. In this way it is possible to test qualitatively an algorithm, a practice and/or an idea in a simple manner using data from the public domain. First, the prediction power of ADME (Absorption Distribution Metabolism Excretion) modules was tested using different classes of marketed drug compounds for the QikProp software suite. It was found that this approach gives one a good idea about which modules deserve further attention for evaluation. Second, a database of 1070 marketed drug compounds was compiled and analyzed in order to assess the occurrence of moieties described in the literature as ‘‘undesirable’’ for high-throughput screening compound libraries due to their ability to perturb assay formats. The study revealed that a total of 277 compounds, 26% of the database, contained at least one of the moieties. In general, it can be concluded that compounds with ‘‘undesirable’’ moieties should not simply be eliminated from compound screening libraries but rather be flagged as potentially problematic. Third, marketed drug compounds are used to evaluate the idea of excluding parent structures of the nitrenium ion (aryl-amine/nitro compounds) as well as sulphur and halogen containing molecules from screening compound collections. Molecules containing such moieties and/or atoms have biological and physiochemical properties, which possibly make them less attractive as leads in drug development. It was found that precursors to the nitrenium ion were relatively abundant in known drug space at 14%. Thus, their simple elimination from drug-like chemical space is not advisable. Furthermore, 24% of drugs investigated contained sulphur atoms and around 28% were halogenated. As some sulphur containing moieties were abundant whilst others were scarce, it was deduced that it would be more effective to eliminate specific molecular scaffolds rather than all sulphur containing molecules. In conclusion, it has been shown that by statistically analysing known drug space a better understanding of the boundaries of drug-like chemical space was established which can help medicinal chemists in finding rewarding regions of chemical space.
