Small chemicals with inhibitory effects on PtdIns(3,4,5)P3 binding of Btk PH domain

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 17μM 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.