Targeted and Focused Library Design in Compound Management

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Konrad Koehler

Pharma IQ spoke with Konrad Koehler, Principal Scientist at Karo Bio about the exploitation of privileged structures in the design of nuclear receptor targeted libraries.

Pharma IQ: What’s particularly new and exciting in this sector of the industry?

Konrad Koehler: Chemogenomics is an industrialized method which reuses compounds, assays and knowledge to efficiently drive drug discovery within a particular target family. Large integrated pharmaceutical companies have become target agnostic and increasingly rely on small biotech companies to provide expertise in specific target families.These industry trends provide an opportunity for specialized target family companies that can deliver innovative drug candidates to fill big pharma’s drug development pipeline.

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Karo Bio is a drug discovery and development company that works within the field of nuclear receptors. We have adopted a chemogenomics approach where we opportunistically explore the nuclear receptor target family through library screening. Medicinal chemistry optimization of the resulting screening hits is then used to develop drug candidates that address a broad range of therapeutic indications.

Pharma IQ: Can you tell us a little about the work that you are doing at Karo Bio in Library Design?

Konrad Koehler: As the starting point for drug discovery, our screening library is one of our primary assets. Through a combination of compounds synthesized for previous nuclear receptor projects, serendipitous discovery of privileged core structures that bind to multiple nuclear receptors, and augmentation of our screening library by systematic expansion of these privileged cores, we have produced a targeted nuclear receptor screening library that provides good coverage of the entire nuclear receptor family as well as a rich source of screening hits for previously unexplored members of the family.

As part of this systematic expansion, we rely on crystallographic structures of representative members of the nuclear receptor family to rationally guide the design of an optimal screening library. An important criteria besides enhanced hit rates is the developability of the screening hits into leads with appropriate ADME characteristics. Because of the hydrophobic nature of nuclear receptor binding cavities, ligands that bind to these receptors also tend to be hydrophobic. Therefore we try to maximize available hydrogen bonding opportunities as revealed by the crystallographic structures to increase the water solubility of the compounds in our screening collection.

Pharma IQ: Can you perhaps tell us a little about your role in the exploitation of privileged structures in the design of nuclear receptor targeted libraries?

Konrad Koehler: My main role at Karo Bio has been structure guided optimization of nuclear receptor screening hits into leads and lead optimization. As the amount of screening (and counter screening) data and crystallographic structures has steadily increased over years, this has provided me an exciting opportunity to increase my focus on rational optimization of our screening library.

Pharma IQ: What challenges do you face and how are you getting around these?

Konrad Koehler: We already have achieved high hit rates and good coverage within the nuclear receptor family. The next hurdle is to provide screening compounds with enhanced selectivity for individual targets within the nuclear receptor family and also selectivity for nuclear receptors vs. other target families such as GPCRs, ion channels, kinases, and proteases. Identification of privileged structures that are inherently selective for the nuclear receptor family is one path that we are actively pursuing. Filtering using multi category Bayesian models trained on broad screening panels is another possible solution.

Pharma IQ: What are you looking forward to most at this year’s Compound Libraries conference?

Konrad Koehler: Exchanging ideas with colleagues from other companies. We have learned a few things that work well with nuclear receptors, but there are clearly lessons to be learned from other target families as well as alternative technological approaches.