Medicinal chemistry meets systems biology：药物化学和系统生物学.ppt

An example – BioFocus library TPF11 * CONFIDENTIAL Medicinal chemistry meets systems biology John Harris, cjh Consultants (Founder and consultant to BioFocus) “Cutting Edge Approaches to Drug Design” MGMS, March 2009 School of Oriental and African Studies, University of London Why should drug discoverers bother about biological networks? nearly all drugs can hit more than one effector target in an organism not all “non-target” effectors are off-targets, metabolic systems or transporters accumulated genomic/proteomic/analytical pharmacological knowledge confirm that several highly efficacious drugs exert their overall therapeutic effect through a network of effectors the output of the network determines the drug profile (i.e. its good points and its bad points) How should they respond to the challenges of biological networks? 1970-1990 – clinical success driven by selectivity for single targets (e.g. h2 antagonists, AII inhibitors). Medchem is driven by isolated enzyme assays or analytical pharmacology. 1990-2000 – as therapeutic targets become more challenging, high-throughput screening, fed by massively combinatorial chemistry, drives expectations upwards – BUT the same technology demands assay systems even less related to the constituted organism! 2000- 2005 – unmet expectations drive a much more focused approach to screening but compounds are still, essentially, optimised against single reductionist assays. 2005- present – increasing realisation that reductionist assays do not predict cell network responses – primary cell screening begins to gain ground. most of the clinically effective antipsychotics require polypharmacological mechanisms (clozapine, a broad-spectrum biogenic amine ligand, is as effective as 5HT2a selective “atypical” antipsychotics such as olanzapine, ziprasidone, etc. (see Roth et al., 2004NatureRevDrugDiscovery353) in anti-infective therapy, polypharmacology is common, e.g. Wellcome’s Septrin (trimethoprim and sulfamethoxaz