Drug Design for mutant Vitamin D receptor

突变维生素 D 受体的药物设计

• 批准号: 17590100
• 负责人: KURIHARA Masaaki
• 金额: $ 2.24万
• 依托单位: National Institute of Health Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590100/
• 关键词: vitamin D_3 analogues; vitamin D receptor; hereditary vitamin D-resistant rickets; docking study; ノンセコ型リガンド

Vitamin D receptor (VDR) belongs to the steroid/thyroid hormone nuclear receptor superfamily. The X-ray crystal structure of the ligand binding domain (LBD) of VDR with 1α,25-dihydroxyvitamin D_3 was determined by Moras et al. in 2000 and the binding mode between ligands and LBD-VDR was revealed.Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1α,25-dihydroxyvitamin D_3 [1α,25(OH)_2D_3]. We found that the A ring-modified analogues, 2α-(3-hydroxypropyl)-and 2α-(3-hydroxypropoxy)-1α,25(OH)_2D_3, (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1α-hydroxyl group of 1α,25(OH)_2D_3. We have also studied on docking models.

维生素D受体（VDR）属于类固醇/甲状腺激素核受体超家族。2000年Moras等测定了维生素D受体与1α，25-二羟维生素D_3的配体结合结构域（LBD）的X射线晶体结构，揭示了配体与LBD-VDR的结合方式。25（OH）_2D_3]。我们发现A环修饰的类似物2α-（3-羟丙基）-和2α-（3-羟丙氧基）-1，25（OH）_2D_3（O1C_3和O2C_3）能比天然激素更好地与突变体VDR（R274 A）结合，该突变体与HVDRR突变体R274 L相似，失去了与1α，25（OH）_2D_3的1α-羟基的氢键。我们还研究了对接模型。

项目成果

Controlling the helical screw sense of oligopeptide by alpha-amino acid side-chain chirality

通过α-氨基酸侧链手性控制寡肽的螺旋方向

• 期刊: Peptides 2004 (in press)
• 作者: M.Shindo;K.Matsumoto;K.Shishido;Manabu Yamakuchi;M.Tanaka
• 通讯作者: M.Tanaka

Computational study on conformation of oligopeptides controlled by side chain chiralities of α-amino acids

α-氨基酸侧链手性控制寡肽构象的计算研究

• 发表时间: 2005
• 期刊: Peptide Science 2004
• 作者: M.Kurihara;et al.
• 通讯作者: et al.

N-Linked oligosaccharide processing enzymes as molecular targets for drug discovery.

N-连接寡糖加工酶作为药物发现的分子靶点。

• 发表时间: 2006
• 期刊: J. Appl. Glycosci. 53
• 作者: Komohara Y;Itoh K;et. al.;W.Hakamata et al.
• 通讯作者: W.Hakamata et al.

Chiral Cyclic α,α-Disubstituted α-Amino Acids Bearing Two Chiral Centers and Conformation of Their Peptides

带有两个手性中心的手性环状α,α-二取代α-氨基酸及其肽的构象

• 发表时间: 2006
• 期刊: Peptide Science 2005 (In press)
• 作者: M.Nagano;et al.
• 通讯作者: et al.

Synthesis of Various Chiral Cyclic α,α-Disubstituted Amino Acids and Conformational Analysis of Their Peptides

多种手性环状α,α-二取代氨基酸的合成及其肽的构象分析

• 发表时间: 2006
• 期刊: Peptide Science 2005 (In press)
• 作者: N.Kawabe;et al.
• 通讯作者: et al.