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Protein kinases are deeply involved in immune-related diseases and various cancers. They are a potential target for structure-based drug discovery, since the general structure and characteristics of kinase domains are relatively well-known. However, the ATP binding sites in protein kinases, which serve as target sites, are highly conserved, and thus it is difficult to develop selective kinase inhibitors. To resolve this problem, we performed molecular dynamics simulations on 26 kinases in the aqueous solution, and analyzed topological water networks (TWNs) in their ATP binding sites. Repositioning of a known kinase inhibitor in the ATP binding sites of kinases that exhibited a TWN similar to interleukin-1 receptor-associated kinase 4 (IRAK4) allowed us to identify a hit molecule. Another hit molecule was obtained from a commercial chemical library using pharmacophore-based virtual screening and molecular docking approaches. Pharmacophoric features of the hit molecules were hybridized to design a novel compound that inhibited IRAK4 at low nanomolar levels in the in vitro assay.

Autotaxin (ATX) is a potential drug target that is associated with inflammatory diseases and various cancers. In our previous studies, we have designed several inhibitors targeting ATX using computational and experimental approaches. Here, we have analyzed topological water networks (TWNs) in the binding pocket of ATX. TWN analysis revealed a pharmacophoric site inside the pocket. We designed and synthesized compounds considering the identified pharmacophoric site. Furthermore, we performed biological experiments to determine their ATX inhibitory activities. High potency of the designed compounds supports the predictions of the TWN analysis.

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Factor XIa (FXIa) is an enzyme that is activated during the earliest stage of initiation of the intrinsic pathway of the blood coagulation mechanism. In this study, we attempted to discover a new FXIa inhibitor based on structure-based molecular modeling. We found that compound 16 exhibits satisfactory predicted properties while maintaining important binding interactions with FX1a. ExperimentalDocking Study. To find a new FX1a inhibitor, we carried out a docking study of selected molecules using the § Contributed equally to this work. Procedure for the Synthesis of 4-(3-Azido-2-benzylpropanamido)-Benzoic Acid Methyl Ester (Scheme 4).2-Benzyl-3-hydroxypropanoic acid, 12 (5 g, 27.70 mmol) in DCM (200 mL) was added to t-butyldimethylsilyl chloride (9.2 g, 61.0 mmol) and imidazole (8.5 g, 124.70 mmol), stirred for 5 h, and extracted, and then ammonium chloride was added (20 mL) and again extracted with DCM (20 mL × 2). After LiOH (554 mg, 13.2 mmol) was added, the reaction mixture was stirred for 2 h, extracted with ethyl acetate (20 mL × 2), recrystallized with diethyl ether (5 mL), and 13 (8.7 mg, 99%) was obtained. And then, DIPEA (188 μL, 1.08 mmol) and PyBOP (2.3 g, 4.40 mmol) were added to 13 (1 g, 3.39 mmol) in DCM (20 mL). This solution was stirred for 6 h, and the reaction mixture was extracted with ethyl acetate (20 mL × 2). TBAF (0.5 mL, 0.48 mmol) was added Scheme 2. Synthesis of tert-butyl (1-azido-3-phenylpropan-2-yl) carbamate. (a) Ms 2 O, TEA, NaN 3 , rt. Scheme 3. Synthesis of compounds 9-11. (a) (1-Azidomethyl-3-methyl-pent-3-enyl)-carbamic acid tert-butyl ester, CuSO 4 , sodium ascorbate, DMSO:H 2 O, rt; (b) 4 M HCl, DCM, rt; (d) p-R-benzoic acid, PyBOP, DIPEA, DMF, rt. Scheme 6. Synthesis of benzyl-(2-hydroxyimino-ethyl)-carbamic acid tert-butyl ester/(2-hydroxyimino-ethyl)-phenethyl-carbamic acid tert-butyl ester. (a) Ethyl

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