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
書誌事項
- 公開日
- 2013-11
- 資源種別
- journal article
- 権利情報
-
- https://www.elsevier.com/tdm/userlicense/1.0/
- https://www.elsevier.com/legal/tdmrep-license
- DOI
-
- 10.1016/j.bmc.2013.08.036
- 公開者
- Elsevier BV
この論文をさがす
説明
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.
収録刊行物
-
- Bioorganic & Medicinal Chemistry
-
Bioorganic & Medicinal Chemistry 21 (21), 6506-6522, 2013-11
Elsevier BV
