Targeting drug resistance: Identifying allosteric binding sites, exploiting conserved allosteric networks with enhanced sampling computational method

针对耐药性：识别变构结合位点，通过增强采样计算方法利用保守的变构网络

• 批准号: 2326434
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2326434
• 关键词: Targeting; drug; resistance; Identifying; allosteric

The problem of drug resistance is common to many targets, including anti-microbial and anti-cancer targets (e.g. kinases). It is increasingly clear that allosteric inhibitors, alone or in combination with orthosteric ones can be used to modulate targets harboring drug-resistant inducing mutations. This 4 year PhD research project, is a collaboration between the UCL Chemistry Department and Institute of Structural and Molecular Biology at UCL and AstraZeneca Ltd, a global biopharmaceutical company. The aim of this EPSRC CASE PhD project is to further optimize the simulation methodologies from the Gervasio's group and apply them to understand the allosteric regulation of Drug resistant targets such as Beta-lactamases (antimicrobial resistance) and anticancer-tagets harbouring drug-resistance inducing genetic mutations. The emergence of drug resistance is one of the most serious problems for global health care, requiring innovative solutions in the design of drugs. Here we will use enhanced sampling simulations to understand the molecular mechanisms of allosteric regulation in these targets

耐药性的问题对于许多靶标是常见的，包括抗微生物和抗癌靶标（例如激酶）。越来越清楚的是，变构抑制剂，单独或与正构抑制剂组合，可用于调节携带耐药诱导突变的靶标。这个为期4年的博士研究项目是UCL化学系和UCL结构与分子生物学研究所与全球生物制药公司阿斯利康有限公司之间的合作。这个EPSRC CASE博士项目的目的是进一步优化Gervasio小组的模拟方法，并将其应用于了解耐药靶点的变构调节，如β-内酰胺酶（抗菌药物耐药性）和携带耐药诱导基因突变的抗癌靶点。耐药性的出现是全球卫生保健面临的最严重问题之一，需要在药物设计中找到创新解决方案。在这里，我们将使用增强的采样模拟，以了解这些目标的变构调节的分子机制