Oral Presentation 10th Australian Peptide Conference 2013

Molecular Obesity, potency and other addictions and challenges drug discovery, with a special focus on PPI and peptide related issues (#30)

Mike Hann 1
  1. Molecular Discovery Research, GlaxoSmithKline, Stevenage, UK

This presentation reflects on some of the learnings of recent years in relation to the causes of attrition in drug discovery and looks at the particular challenge of Protein-Protein Interactions and Peptides as sources of inspiration for and translation into drugs.

Despite the increase in global biology and chemistry knowledge, the discovery of effective and safe new drugs seems to become harder rather than easier. Some of this challenge is due to increasing demands for safety and novelty, but some of the risk involved in this and the consequential attrition should be controllable if we had more effectively learnt from our failures. The term Molecular Obesity has been introduced to describe the tendency to build potency into molecules by the inappropriate use of lipophilicity which leads to the premature demise of drug candidates. The challenge of PPI and peptide derived drugs is further compounded by the need for cellular access of many targets of interest which again is in conflict with the size of molecules typically active in this domain of drug discovery.  The emergence of and role of indices to help in drug discovery will be discussed as will ways of understanding the chemical tractability of targets. The challenge of understanding the concentration of drug molecules at the site of action will also be discussed as this is another critical issue for understanding dose related and hence ADMET issues.

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  2. Hann, M. M. Molecular obesity, potency and other addictions in drug discovery. MedChemComm (2011), 2(5), 349-355
  3. Hann, M. M.; Leach, A. R.; Burrows, J. N.; Griffen, E. Lead discovery and the concepts of complexity and lead-likeness in the evolution of drug candidates. Comprehensive Medicinal Chemistry II (2006), 4 435-458
  4. Leach, AR.; Hann, MM.; Burrows, JN.; Griffen, EJ. Fragment screening: an introduction. . Molecular BioSystems (2006), 2(9), 429-446. Publisher: Royal Society of Chemistry
  5. Hann, MM.; Oprea, TI. Pursuing the leadlikeness concept in pharmaceutical research. Current Opinion in Chemical Biology (2004), 8(3), 255-263
  6. Hann, MM.; Leach, AR.; Harper, G. Molecular Complexity and its impact on the probability of finding leads for Drug Discovery. Journal of Chemical Information and Computer Sciences (2001), 41(3), 856-864