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Concepts

Recognising and addressing the limitations of past HTS campaigns:

expanding diversity in the druggable chemical space

The aim of any anti-trypanosomatid drug development initiative is to bring a small molecule  together with a chemically tractable protein target that will potently and selectively inhibit  parasite survival in vivo. Molecules targeting intracellular functions must actively or passively  cross the protozoan cell wall and accumulate at their site of action without first being  detoxified by metabolic enzymes, nor should they be cytotoxic to the host. Most drug  discovery projects fail because the biological target is either not druggable or sufficiently  selective, thus potent safe and bioavailable lead compounds are hard to identify.  Our primary  objective as a consortium will be to implement a coherent (integrated) approach to populate  and advance all stages of the anti-trypanosomatid drug pipeline using a combination of  iterative physiological and target-based screening procedures, combining foremost academic  efforts with industry leaders in fragment- based drug design and medicinal chemistry.   The primary challenge to find such rare drug entities is the sheer number of potential  molecular structures that can fit the drug-like chemical space, with an estimated 1062  theoretical compounds conforming to Lipinski’s empirical Rule  of Five. This exceeds the most enthusiastic screening campaign  by a mind-boggling factor. Even the largest corporate screening  libraries of >106 compounds can cover only a miniscule part of  this vast chemical space, with considerable redundancy existing  between overlapping chemotypes. Worse still, many  compounds selected on the basis of potency in HTS of diversity  oriented libraries suffer high rates of attrition due to undesirable  physicochemical or pharmacological properties.  By contrast,  screening of smaller compound fragments (120–250 Da)  optimised for their drug-like properties will increase hit rates  substantially since their lower molecular complexities increase  the probability of a productive interaction with a target.  Furthermore, such fragment libraries cover a much larger proportion of the chemical space  thereby increasing protein-drug interaction diversity by several orders of magnitude. Although  fragments bind with lower affinity than their larger HTS counterparts, they typically show  higher ligand binding efficiency (binding affinity per heavy atom) and are increasingly seen as  the starting point of choice in new drug discovery campaigns. Combining multiple non-  overlapping fragments often results in additive binding free energies, allowing drugs to be  sought as fragmented pieces selected on the basis of optimal drug-like features, then joined  together judiciously to produce a higher affinity parent molecule with tailored pharmacological  characteristics. Fragments will be screened directly in cell extracts using high concentration  bioassays (PHX) or for chosen recombinant proteins utilising NMR (USTA), SPR (GFTY) or  thermal shift analysis (USTA). Additionally, co-crystallisation of the protein target with multiple  low affinity fragments provides ideal starting points for potency improvements via in silico  design (NOVA).  The combined medicinal chemistry expertise of the SME and academic  partners, the availability of numerous validated targets and knowledge of drug bioavailability  will enable KINDReD to create a new generation of highly selective bioactive compounds  against this group of parasitic protozoans.  

Scientific programme

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© IP Research Consulting 2014
Concepts