Human Drug Efficacy Targets

Following completion of the first phase of the Human Genome Project, Craig Venter and colleagues10 observed that about 18% of the putative proteins represented in the human genome belonged to chemically defined families nominally regarded as major drug targets. The analysis by these investigators also identified sequences for receptors and select regulatory molecules, for transferase and oxidoreductase enzymes, kinases, ion channels, and transporters. On further analysis of these data, Jurgen Drews concluded that there were 5000-10,000 potential drug targets in the human genome, and that approved medicines exploited fewer than 500 of these as validated targets.11

Assignment of Drug Efficacy Targets

Hopkins and Groom12 challenged Drews's estimate and suggested that rule-of-five* compliant drugs acted primarily through only 120 targets. In a subsequent

*Rule-of-five: Poor absorption or permeation of a compound is more likely when there are more than five hydrogen bond donors, the molecular mass is greater than 500, the calculated octanol/water partition coefficient (c log P) is greater than 5, and the sum of nitrogen and oxygen atoms in a molecule is greater than 10. Many drugs are exceptions to this rule and often these are substrates for biological transporters.

report, Hopkins and colleagues reconciled these and other earlier reports through analysis of more than 21,000 drug products and reached a consensus of 324 molecular drug targets for all classes of approved therapeutic agents.13 When products with duplicate active ingredients, supplements, vitamins, imaging agents, and so on were removed, only 1357 unique drugs remained, of which 1204 were ''small molecule drugs'' and 166 were ''biological drugs.'' Among all small molecule drugs, 885 (74%) passed the rule-of-five test and at least 192 (16%) of them were prodrugs.

Protein molecular targets could be assigned to 1065 (78%) of the 1357 unique drugs via a comprehensive analysis of the literature. When possible, the particular binding domain of the protein as well as the binding residues was also assigned. Among the 324 molecular targets, 266 were found to be human genome-derived proteins; the remainder comprised nonhuman (bacterial, viral, fungal, or other pathogenic organism) targets. Small molecule drugs were found to modulate 248 proteins, of which 207 were targets encoded by the human genome. Oral, small molecule drugs targeted 227 molecular targets, of which 186 were human targets. Biological drugs, on the other hand, targeted 76 proteins with monoclonal antibody therapeutics acting on 15 distinct human targets. Only nine targets were found to modulate both small molecule and biological drugs. For example, the biological drugs cetuximab and panitumumab target the extracellular domain of the receptor tyrosine kinase epidermal growth factor receptor (EGFR) (ERBB1), whereas the small molecule drugs gefinitib and erlotinib target the adenine portion of the ATP-binding site of the cytosolic catalytic kinase domain of the same receptor.

Many drugs are capable of interacting with more than one valid target and exhibit clinically relevant, multitarget effects. Members of the class of protein kinase inhibitors encoded by the BCR=ABL fusion gene, such as the small molecule drug imatinib mesylate (Gleevec®), provide excellent examples of such ''clinical polypharmacology.'' Following the introduction of imatinib for the treatment of chronic myeloid leukemia, studies revealed that it targets kinases other than BCR/ABL such as c-Kit, expanding its clinical relevance in myeloid disorders to gastrointestinal stromal tumors and glioblastomas. The clinical polypharmacology of imatinib and newer protein kinase inhibitors such as sor-afenib and sunitinib with target footprints similar to imatinib can be rationalized by similarities of key pharmacophores.{ Recent research on such polyphar-macological interactions reveals the extent of clinically relevant drug promis-cuity.14 Taking account of polypharmacological interactions and putting them on a sound footing represent other major challenges to the discovery of safe and effective clinical therapies.

^Pharmacophore: An ensemble of steric and electronic features that is required to ensure optimal interactions with a specific target structure and to trigger (or block) its biological response.

Gene Families as Drug Targets

A large number of receptor superfamilies encompassing both membrane receptors [e.g., G-protein-coupled receptors (GPCRs), tyrosine kinase receptors, ligand- and voltage-gated ion channels, and integrins] and intracellular nuclear receptors have evolved to accommodate the selective recognition of a large and diverse number of endogenous and exogenous ligands. Analysis of the gene-family distribution of drug targets for both small molecule and biological drugs by Overington and colleagues revealed that more than 50% of drugs targeted only four key gene families: Class I GPCRs, nuclear receptors, ligand-gated ions channels, and voltage-gated ion channels (Figure 10.2). Several additional features of gene-family targets for current drugs are brought out by the analysis of Overington et al. (1) Approximately 130 ''druggable'' domains cover all current drug targets, a number that contrasts markedly with the number of protein families (>16,000) and protein folds 10,000). (2) Approximately 60% of current drug targets are located at the cell surface, compared with only ^22% of all proteins in the human genome. (3) Only 1620 distinct human protein sequences are linked directly to a genetic disease. Of these, 105 are drug targets, corresponding to 47% of human drug targets that are directly linked with a disease. (4) The determination of the potency distribution of marketed small molecule drugs shows that the median affinity for all current small molecule drugs is around 20 nM. (5) Analysis of the protein domains shows that new domains join the drugged domain set relatively infrequently. For example, of 361 new molecular entities (NMEs) approved by the FDA between 1999 and 2000, 76% targeted a previously drugged domain and only 6% targeted a previously undrugged

Remaining drugged families and singletons (32.8%)

Type II DNA topoisomerase (1.9%) [] Fibronectin type III (2.1%) [] Type II DNA topoisomerase (2.3%) [] Sodium neurotransmitter symporter family (2.7%) Q Myeloperoxidase-like enzymes (3%) O Penicillin-binding proteins (4.1%) □

□ Voltage-gated ion channels (5.5%) Ligand-gated ion channels (7.9%) Nuclear receptors (13%) Rhodopsin-like GPCRs (26.8%)

Figure 10.2 Gene family distribution (percentage drugs/drug target).

domain; the remainder had either unknown targets (4%) or were believed not to act at distinct molecular targets (17%). (6) The rate of target innovation averaged 5.3 new drugged targets per year but was quite variable year by year.

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