Conformational restriction approach to β-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations
| Autor: | Hidekuni Yamakawa, Yoshikazu Tanaka, Toru Nakano, Takahiko Yamamoto, Kazunari Hattori, Kenichiro Fujiwara, Satoshi Shuto, Shuji Yonezawa, Hiroshi Takemoto, Mitsuhiro Arisawa, Motoko Hosono, Chie Muto |
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| Rok vydání: | 2013 |
| Předmět: |
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Molecular Ethylene Stereochemistry Clinical Biochemistry Molecular Conformation Pharmaceutical Science Crystal structure Calorimetry Crystallography X-Ray Biochemistry Cyclopropane Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Hydrolase Aspartic Acid Endopeptidases Humans Protease Inhibitors X ray analysis Molecular Biology Binding Sites Organic Chemistry Stereoisomerism Isothermal titration calorimetry Amides Protein Structure Tertiary Crystallography chemistry β secretase Thermodynamics Molecular Medicine Amyloid Precursor Protein Secretases Linker Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:6506-6522 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2013.08.036 |
| Popis: | For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring. |
| Databáze: | OpenAIRE |
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