カーバ・サイクロフェリトールは中性保持グルコシダース阻害剤である
Thomas J M Beenakker, Dennis P A Wander, Wendy A Offen1
1Department of Chemistry, University of York , Heslington, York, YO10 5DD, U.K.
Journal of the American Chemical Society
|May 3, 2017
まとめ
新しいカーバ・サイクロフェリトール阻害剤を設計し 酵素の変異状態を模倣して サーモトーガ・マリティマTmGH1β-グルコシダースを強力に抑制しました
科学分野:
- 生物化学
- 酵素阻害剤の設計
- コンピュータ化学
背景:
- グリコシダゼは,様々な生物学的プロセスに関与する重要な酵素です.
- グリコシダースの特異的阻害剤の開発は,治療用途において重要である.
- トランジション状態模倣は強力な酵素阻害剤を設計する成功戦略です.
研究 の 目的:
- 維持 β-グルコシダース阻害剤として新しいカルバ-サイクロフェリトール類を設計し,合成する.
- 計算方法を用いてサイクロプロピル阻害剤の形状的好みを調査する.
- Thermotoga maritimaのTmGH1β-グルコシダゼに対する新薬の抑制作用を評価する.
主な方法:
- Ab initioメタダイナミクスのシミュレーションで,コンフォメーションの自由エネルギー風景を分析する.
- カルバ・サイクロフェリトールとN- ((4-アジドブチル) カルボキシアミドを合成する.
- 酵素阻害測定と3D構造分析
主要な成果:
- シミュレーションにより,サイクロプロピル阻害剤における4H3移行状態構成の強いバイアスが明らかになった.
- カーバ・サイクロフェリトールは,8. 2nMのKiでTmGH1β-グルコシダースの強力な阻害を示した.
- 構造分析により,H3形状の結合が確認され,設計戦略が検証された.
結論:
- カーバ・サイクロフェリトールの類型は,Thermotoga maritima TmGH1β-グルコシダースの強力な阻害剤である.
- サイクロプロピルユニットによって誘発されるコンフォメーションストレンは,阻害剤の結合親和性を高めます.
- このアプローチは,新しい,緊密に結合する酵素阻害剤を開発するための有望な戦略を提供します.
関連する概念動画
Oral Hypoglycemic Agents: α-Glucosidase Inhibitors
684
α-glucosidase inhibitors, including acarbose (Precose), miglitol (Glyset), and voglibose (Voglib) (primarily available in Asia), are drugs that control blood sugar levels by delaying the digestion of starch and disaccharides. They achieve this by inhibiting α-glucosidase enzymes in the intestine, which slow the absorption of carbohydrates in the intestine, which in turn leads to a prolonged release of the glucoregulatory hormone GLP-1 from intestinal L-cells.
Acarbose and miglitol are...
Acarbose and miglitol are...
684
Dipeptidyl Peptidase 4 Inhibitors
787
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
787
Oral Hypoglycemic Agents: Biguanides and Glitazones
739
Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood...
739
Oral Hypoglycemic Agents: Glinides
760
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
760
Glucagon-like Receptor Agonists
1.1K
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
1.1K
Bioavailability Enhancement: Drug Stability Enhancement and GI Retention
281
Improving a drug's stability in the gastrointestinal (GI) tract is paramount for enhancing its bioavailability and therapeutic effectiveness. Various strategies are employed to protect the drug from the harsh gastric milieu and to ensure its release and absorption at the desired site within the GI tract.Polymer coatings are one such method used to shield drugs from the stomach's acidic environment. By preventing premature drug release, these coatings improve the bioavailability of unstable...
281


