Uncovering molecular bases underlying bone morphogenetic protein receptor inhibitor selectivity was written by Alsamarah, Abdelaziz;LaCuran, Alecander E.;Oelschlaeger, Peter;Hao, Jijun;Luo, Yun. And the article was included in PLoS One in 2015.Computed Properties of C25H22N6 This article mentions the following:
Abnormal alteration of bone morphogenetic protein (BMP) signaling is implicated in many types of diseases including cancer and heterotopic ossifications. Hence, small mols. targeting BMP type I receptors (BMPRI) to interrupt BMP signaling are believed to be an effective approach to treat these diseases. However, lack of understanding of the mol. determinants responsible for the binding selectivity of current BMP inhibitors has been a big hindrance to the development of BMP inhibitors for clin. use. To address this issue, we carried out in silico experiments to test whether computational methods can reproduce and explain the high selectivity of a small mol. BMP inhibitor DMH1 on BMPRI kinase ALK2 vs. the closely related TGF-尾 type I receptor kinase ALK5 and vascular endothelial growth factor receptor type 2 (VEGFR2) tyrosine kinase. We found that, while the rigid docking method used here gave nearly identical binding affinity scores among the three kinases; free energy perturbation coupled with Hamiltonian replica-exchange mol. dynamics (FEP/H-REMD) simulations reproduced the absolute binding free energies in excellent agreement with exptl. data. Furthermore, the binding poses identified by FEP/HREMD led to a quant. anal. of phys./chem. determinants governing DMH1 selectivity. The current work illustrates that small changes in the binding site residue type (e.g. pre-hinge region in ALK2 vs. ALK5) or side chain orientation (e.g. Tyr219 in caALK2 vs. wtALK2), as well as a subtle structural modification on the ligand (e.g. DMH1 vs. LDN193189) will cause distinct binding profiles and selectivity among BMP inhibitors. Therefore, the current computational approach represents a new way of investigating BMP inhibitors. Our results provide critical information for designing exclusively selective BMP inhibitors for the development of effective pharmacotherapy for diseases caused by aberrant BMP signaling. In the experiment, the researchers used many compounds, for example, 4-(6-(4-(Piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline (cas: 1062368-24-4Computed Properties of C25H22N6).
4-(6-(4-(Piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline (cas: 1062368-24-4) belongs to piperazine derivatives. Piperazine is a fairly basic compound and is an amine solvent. Outside the body, piperazine has a remarkable power to dissolve uric acid and producing a soluble urate, but in clinical experience it has not proved equally successful. Computed Properties of C25H22N6
Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics