Small chemicals with inhibitory effects on PtdIns(3,4,5)P3 binding of Btk PH domain |
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| Institution: | 1. Sakarya University, Arts and Sciences Faculty, Department of Physics, 54187, Sakarya, Turkey;2. Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan;3. School of Chemistry, University of Manchester, Manchester, M30 9PL, UK;1. School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK;2. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;1. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;2. Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China;3. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, 04318 Leipzig, Germany;4. PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA;1. Università degli Studi di Milano, Dipartimento di Chimica, Via Golgi 19, I-20133 Milan, Italy;2. Fondazione IRCCS Istituto Nazionale dei Tumori, Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Via Amadeo 42, I-20133 Milan, Italy |
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| Abstract: | Phosphatidylinositol-3,4-5-triphosphates (PtdIns(3,4,5)P3) formed by phosphoinositide-3-kinase (PI3K) had been known as a signaling molecule that plays important roles in diverse cellular processes such as cell signaling, metabolism, cell differentiation, and apoptosis. PtdIns(3,4,5)P3 regulates diverse cellular processes by recruiting effector proteins to the specific cellular locations for correct functions. In this study, we reported the inhibitory effect of small chemicals on the interaction between PtdIns(3,4,5)P3–Btk PH domain. Small chemicals were synthesized based on structural similarity of PtdInsP head-groups, and tested the inhibitory effects in vitro via surface plasmon resonance (SPR). As a result, the chemical 8 showed highest inhibitory effect with 17 μM of IC50 value. To elucidate diverse inhibitory effects of different small chemicals we employed in silico docking experiment using molecular modeling and simulation. The result of docking experiments showed chemical 8 has more hydrogen bonding with the residues in PtdIns(3,4,5)P3 binding site of Btk PH domain than others. Overall, our studies demonstrate the efficient approach to develop lipid binding inhibitors, and further we can use these chemicals to regulate effector proteins. In addition, our study would provide new insight that lipid binding domain may be the attractive therapeutic targets to treat severe human diseases. |
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| Keywords: | Btk PH domain In silico docking Small chemicals |
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