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Class of Drug No. Molecular •Orange book, 2005 Target Targets Targets of approved 301 •26,000 drugs products which NMEs (Human and anti- reduces to 1783 unique new infectives) Human Targets of 238 molecular entities approved NMEs •of which 1415 are small molecule Human Targets of 170 chemical entities approved NCEs Targets of approved 59 •180 are biological therapeutics biologicals •18 of which are antibodies Human Targets of 15 approved antibodies
Molecular Targets of Current Drugs
By Drug Substance By Target rhodopsin-like rhodopsin-like GPCR GPCR 20.4% nuclear receptor Nuclear receptor ligand-gated ion channel + 40.6% Na /neurotransmitter 6.5% cytochrome p450 symporter 3.1% cytokine receptor, ligand-gated ion 4.5% 2.7% type 1 channel 6.7% S1 serine proteinase voltage-gated 7.3% 11.1% Na+/Ca2+ channel phosphodiesterase Data: Derived from DrugStore database by John Overington, Inpharmatica Ltd Non- Ro5 7DUJHWVZLWK/HDGV redundant Non- *HQH)DPLO\ human targets redundant <10uM human Targets <10uM Aminergic GPCRs 34 34 GPCRs Class B Aspartyl Proteases 7 3 1% Cysteine Proteases 16 14 Kinases- others 1% Enzymes- others 102 81 Others Enzymes- others Aspartyl Proteases 15% 14% GPCRs Class A- others 35 30 1% GPCRs Class C GPCRs Class B 5 2 1% GPCRs Class C 10 10 PDEs 2% Hydrolases 34 28 Protein Kinases Ion Channels- others 11% Ion Channels- Ligand 26 20 2% Gated Cysteine Proteases Ion Channels- others 14 12 2% Nuclear hormone receptors Kinases- others 7 6 3% Peptide GPCRs 7% Metalloproteases 41 39 Ion Channels- Ligand Gated 4% Nuclear hormone 22 19 receptors Serine Proteases 4% Transferases Others 108 79 Hydrolases 6% Oxidoreductases 39 37 5% Metalloproteases Aminergic GPCRs 6% PDEs 11 11 5% Oxidoreductases Peptide GPCRs 52 42 GPCRs Class A- others 6% 5% Protein Kinases 75 66 *HQH)DPLO\GLVWULEXWLRQRIQRQUHGXQGDQW Serine Proteases 27 24 KXPDQSURWHLQVZLWKVPDOOPROHFXOHFKHPLFDO Transferases 42 30 OHDGVZLWKELQGLQJDIILQLWLHV X0'DWD Total 707 587 GHULYHGIURPDQDO\VLVRI\HDUVRISXEOLVKHG G. Paolini 0HG &KHP GDWD 'UXJJDEOH*HQRPH3UHGLFWLRQV
Druggability Prediction No. Molecular Gene family distributions of predicted druggable genome Method Targets GPCRs 21% Targets of approved NCEs 170 GPCRs Kinases Proteases 32% Transporters Sequence homology to NCE 945 Ion Channels drug targets Transferases Other Enzymes Targets of chemical leads with 707 Phosphatases Cytochrome P450 activities (binding affinities) Kinases below 10uM Nuclear Hormone Receptors 15% Phospholipases Targets of Ro5 chemical leads 587 Phosphodiesterases with activities (binding affinities Other Receptors 1% Cell Adhesion <= 10uM) Chemokines Proteases Sequence homology to targets 2921 2% 7% Other/Unclassified with chemical leads* 3% 5% 6% Transporters Feature-based druggability 2325 Ion Channels sequence probability prediction 3.5 Structured-based prediction 427 Druggable 3 genome Sequence homology to proteins 3541 2.5 estimates predicted druggable by 2 increase slowly structure-based method 1.5 due to power Family) 1 Predicted Druggbable Genome 3505 law nature of (high confidence) 0.5 gene family Gene in InterPro Genes of (No populations 10 0 Human Genome Log 0123
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Druggability Prediction Method No. of Molecular targets Targets of approved antibodies 15 1516 genes likely to encode proteins druggable by both small molecules and Targets of approved biologicals 59 protein therapeutics
Secreted protein (high confidence) 1384
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