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DMKPred: Specificity and Cross- reactivity of Kinase Inhibitors Institute of Microbial Technology, Sector-39A, Chandigarh, India G P S Raghava, Head Bioinformatics Centre Email: raghava@imtech.res.in; Web: http://www.imtech.res.in/raghava/raghava@imtech.res.inhttp://www.imtech.res.in/raghava/ Slide 2 Slide 3 Critical components of cellular signal transduction cascades. They regulate cell division, differentiation, proliferation, movement & apoptosis by phosphorylating Ser, Thr and Tyr residues of specific substrates. Represent 1.7 % of all human genes. What are protein kinases ? Slide 4 Why kinases are so important? They are the key regulators of all aspects of neoplasia, including proliferation, invasion, angiogenesis and metastasis. A number of diseases, especially cancer involve unregulated kinase activity (overexpression / upregulation). This makes kinases as important targets for drug development. Kinase inhibitors are successfully used in cancer treatment. Slide 5 Kinase inhibitors Chronic myeloid leukemia (CML) drug molecule bind to the ATP binding site of bcr-abl tyrosine kinase. Slide 6 Alignment of the ATP-binding site residues of kinase proteins Slide 7 Selectivity and specificity of existing kinase inhibitors Slide 8 Can we solve specificity problem of kinase inhibitors ? Fabin et al., Nat. Biotechnol., 2005, 23, 229- 236 Most of the drug molecules binds with other protein kinases and cause cross-reactivity. Its very difficult to design a specific kinase inhibitors against a protein kinase. If K d of inhibitors with primary intended target is 10 fold then chances of cross-reactivity is low. Slide 9 Specificity and cross-reactivity of kinase inhibitors Molecules data: Data was taken from Nat. Biotechnol., 2005, 23, 229-236 (Fabin et al., 119 20 K d data) Select those kinases for which 6 chemical molecules have significant binding Finally we select 29 protein kinases for this study Slide 10 Specificity and cross-reactivity of kinase inhibitors Structure Descriptors: We calculated 8 structure descriptors from Molinspiration (on line web server for descriptor calculation) We also calculated 600 structure descriptors using PreADMET (on line web server for molecular descriptor calculation) Remove insignificant descriptors and select 62 molecular descriptors for further study Slide 11 Specificity and cross-reactivity of kinase inhibitors Slide 12 Correlation between molecular descriptors and K d Select molecular descriptors with highest average correlation Specificity and cross-reactivity of kinase inhibitors Slide 13 ProteinTop 5Top 10Top 15Top 17Molinspiratio n AAK1 0.514NM0.4500.5910.420 ABL1 0.4490.7140.4300.6970.472 ABL1E255K 0.5300.4800.4350.4750.585 ABL1H396P 0.8510.6230.4730.6330.480 ABL1M351T 0.4400.6980.5610.6750.474 ABL1Q252H 0.4720.7190.4910.7060.519 ABL1Y253F 0.4090.7310.4860.7160.444 ABL2 0.7370.6210.4730.6170.440 BIKE 0.2530.381NM0.6690.511 CLK2 0.2820.7630.5230.3600.329 EGFR 0.2870.2790.4760.2260.277 EPHA5 0.4280.4450.3490.5110.464 EPHA6 0.2120.4410.3720.2330.379 EPHB1 0.4620.1950.5780.3940.577 GAK 0.1970.3410.0280.4550.382 JNK2 0.6690.6010.6270.6470.064 JNK3 0.1200.3790.3680.4670.327 KIT0.4300.9080.5180.3660.332 LCK 0.6530.7710.7270.0470.621 MAP4K5 0.6580.5150.4100.1540.129 P38ALPHA 0.3060.5390.8050.4940.735 PDGFR 0.5830.2680.3630.1770.036 RIPK2 0.7360.2490.2500.4400.557 SLK 0.6430.3630.293 0.345 SRC 0.7700.5410.540 0.395 STK10 0.7920.5110.3960.5520.373 STK18 0.2260.4430.2100.4030.529 TNIK 0.5630.2740.2350.2020.514 VEGFR 0.2660.4090.1720.3140.328 Average 0.4820.5070.4300.4500.415 General model for chemical kinase inhibitors Slide 14 Kinase specific model for chemical kinase inhibitors Slide 15 Web interface for DMKPred Slide 16 Computational Resources for Drug Discovery An Insilico Module of Open Source Drug Discovery Slide 17 Slide 18 Slide 19 Slide 20 Slide 21 Slide 22 Slide 23 Slide 24 Slide 25 Slide 26 Meta-Server: Prediction of subcellular localization of proteins using various server Slide 27 URLs: http://www.imtech.res.in/raghava/ & http://crdd.osdd.net/ & bic.uams.edu/