Protein Alpha Shape Similarity Analysis (PASSA): a new method for mapping protein binding sites. Application in the design of a selective inhibitor of tyrosine kinase 2 |
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Authors: | Tøndel Kristin Anderssen Endre Drabløs Finn |
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Affiliation: | (1) Department of Chemistry, Norwegian University of Science and Technology, Sem Selands v. 14, N-7491 Trondheim, Norway;(2) SINTEF, Unimed MR-center, N-7465 Trondheim, Norway |
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Abstract: | We have developed a method that we have called Protein Alpha Shape Similarity Analysis (PASSA), that identifies interaction sites that can be utilised to achieve selectivity towards a protein. We have shown that this method is able to identify residues of tyrosine kinases that interact with known selective inhibitors using the following test cases: Abelson (Abl) kinase in complex with STI-571 and Janus kinase 2 (Jak2) in complex with AG-490. The 3D structures of the tyrosine kinase domains of Tyrosine kinase 2 (Tyk2) and Jak2 have been predicted by homology modelling. Computational docking of AG-490 and a set of tyrphostins known not to inhibit Jak2 indicated that our homology models are able to separate inhibitors from non-inhibitors. PASSA has also been used to identify unique properties of Tyk2. According to our results, interactions with hydrogen acceptors and donors on the following residues can be utilised to achieve selectivity towards Tyk2: Y955, E1053, D1062 and S1063. These residues are placed close to non-conserved hydrophobic pockets. The PASSA results, together with results from Multiple Copy Simultaneous Search (MCSS) were used to suggest functional groups of a selective Tyk2 inhibitor. |
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Keywords: | 3D QSAR alpha shapes drug design homology modelling PLS proteins selectivity tyrosine kinase inhibitors. |
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