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

耐药性问题是许多靶标的共同问题，包括抗微生物和抗癌靶标(例如，激酶)。越来越清楚的是，变构抑制剂可以单独使用或与正构抑制剂联合使用，以调节携带耐药诱导突变的靶点。这个为期4年的博士研究项目是伦敦大学学院化学系、伦敦大学学院结构与分子生物学研究所和全球生物制药公司阿斯利康有限公司的合作项目。这个EPSRC案例博士项目的目的是进一步优化Gervasio团队的模拟方法，并将其应用于了解耐药靶标的变构调节，如β-内酰胺酶(抗菌素耐药)和含有耐药诱导基因突变的抗癌标签。耐药性的出现是全球医疗保健面临的最严重问题之一，需要在药物设计方面创新解决方案。在这里，我们将使用增强的采样模拟来了解这些靶标中变构调节的分子机制。

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