基于激素的虚拟查,分子对接和新β-雌激素受体激活器的分子动态模拟,具有药理肥胖治疗潜力
Domingo Méndez-Álvarez1, Maria F Torres-Rojas2, Edgar E Lara-Ramirez1
1Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Mexico.
Molecules (Basel, Switzerland)
|June 10, 2023
概括
针对雌激素受体β (ERβ) 的新型小分子显示出对控制肥胖的希望. 计算研究确定了稳定,安全的化合物,可能导致新的抗肥胖药物.
科学领域:
- 药理学和药物发现
- 计算化学计算化学
- 内分泌学 在内分泌学.
背景情况:
- 肥胖是一个全球性的健康危机,需要新的治疗策略.
- 雌激素受体β (ERβ) 激活促进体重减轻,为肥胖管理提供了可行的药物标.
- 现有的肥胖治疗方法存在局限性,需要探索新的分子标和候选药物.
研究的目的:
- 识别和预测能够激活雌激素受体β (ERβ) 的新型小分子.
- 通过对FDA批准的药物进行ERβ活性查,探索药物重新定位策略.
- 通过计算方法评估候选分子的稳定性,安全性和潜在有效性.
主要方法:
- 化学数据库 (ZINC15,PubChem,Molport) 的基于联体的虚拟选,使用已知的ERβ联体结构.
- 对FDA批准的药物进行分子对接模拟,以确定潜在的ERβ重新定位候选者.
- 对选定的化合物进行分子动力学模拟和ADMET (吸收,分布,新陈代谢,分泌,毒性) 预测.
主要成果:
- 化合物1,2和6在ERβ活性部位内表现出显著的结合稳定性 (RMSD<3.3 Å).
- 分子动力学模拟证实,这些化合物不会对ERβ的结构完整性或紧性产生不利影响.
- 在基中ADMET分析表明,已识别的化合物具有有利的安全性,这表明毒性低.
结论:
- 该研究成功地确定了具有激活ERβ.潜力的新型小分子.
- 这些ERβ配体表现出有希望的稳定性和安全性,使它们成为进一步药物开发的合适候选者.
- 这些发现表明,用这些新型化合物准ERβ可能为控制肥胖提供新的治疗途径.
相关概念视频
Structure-Activity Relationships and Drug Design
800
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
800
Glucagon-like Receptor Agonists
369
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...
369
Drug Discovery: Overview
8.1K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
8.1K
Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K
G Protein-coupled Receptors
12.3K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
12.3K


