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Computational Design of Inhibitor Specificity

抑制剂特异性的计算设计

基本信息

批准号：
8245085
负责人：
BRUCE TIDOR
金额：
$ 21.43万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-06-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245085
关键词：
Adherence Adoption Affinity Algorithms Binding Binding Sites Biological Assay Case Study Cell Culture Techniques Clinical Collaborations Collection Combined Modality Therapy Communicable Diseases Complex Crystallography Data Development Drug Design Drug resistance Effectiveness Electrostatics Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Freedom Goals HIV HIV Protease HIV Protease Inhibitors HIV-1 Infectious Agent Knowledge Laboratories Lead Ligands Malignant Neoplasms Massachusetts Medical Methodology Methods Molecular Mutate Mutation North Carolina Organic Chemistry Peptide Hydrolases Pharmaceutical Chemistry Pharmacotherapy Procedures Property Proteins Rana Research Design Resistance Resistance profile Resources Series Site Solvents Specificity Structure Testing Time Universities Variant Virus Work base cancer cell design drug development effective therapy flexibility improved infectious disease treatment inhibitor/antagonist medical schools member mutant novel novel strategies patient population pressure prevent public health relevance resistance mutation resistant strain small molecule success therapy development virology

项目摘要

DESCRIPTION (provided by applicant): The development of drug therapies has been an essential approach to the treatment of infectious disease and cancer. High rates of error-prone replication for certain infectious agents and cancer cells can lead to drug resistance on a relatively short time scale. This project will pursue a new approach to the development of enzyme inhibitors that are less prone to the emergence of target resistance, namely the substrate envelope hypothesis, will develop and apply inverse computational design methods for small-molecule ligands, and will test the substrate envelope hypothesis extensively in the context of HIV-1 protease through a collaborative effort with experimental groups expert in organic and medicinal chemistry, enzyme assays, protein crystallography, and virology. HIV protease has been selected as a case study due to the large amount of prior information regarding resistance mutations that have been selected in patient populations and cell culture under the selective pressure of clinical compounds. The substrate envelope hypothesis maintains that inhibitors that reside within the volume shared by substrates are less susceptible to resistance mutations, because such mutants must still turn over substrates. Through our computational approaches we will develop inhibitors for HIV protease with robust binding properties to panels of resistance mutants, and through collaborative work these inhibitors will be synthesized, assayed, and characterized. Preliminary work has demonstrated some success and raised some questions regarding the substrate envelope hypothesis. The proposed project involves the further development of our computational ligand design methodology to achieve the goals of the current work, but the developments are of broad applicability, including the efficient treatment of target site flexibility, the incorporation of additional implicit solvent energy function forms, and the implementation of more efficient search algorithms. The proposed project will stringently test the substrate envelope hypothesis through the fine- scale design of inhibitors that do and do not respect the substrate envelope, including tests to rescue inhibitors that succumb to resistance mutations and that violate the substrate envelope, through the design of variants that respect the envelope. This collection of otherwise identical inhibitors that differ in their adherence to the substrate envelope will be a crucial resource for relating resistance profiles to the envelope hypothesis, which I will study with my experimental collaborators. The proposed project will also design and study the properties of inhibitors predicted to bind broadly to multiple members of a panel of resistance mutants, and compare them to properties of inhibitors predicted to bind narrowly to a single target. In this way, new principles for robust binders and improvements to the substrate envelope hypothesis are likely to result. A particular advantage to implicit design approaches like the substrate envelope hypothesis is that they do not require prior explicit knowledge of drug resistance mutations. PUBLIC HEALTH RELEVANCE: Current medical drug therapy for infectious disease and cancer is limited by the emergence of resistance, in which a previously effective therapy loses its effectiveness, often through mutations in the target. This project aims to study methods for developing new therapies that prevent, or at least significantly delay, the emergence of resistance. Initial work will target the HIV protease, which is the target of some current therapies, but for which the emergence of resistant strains remains a significant problem.

描述（由申请人提供）：药物疗法的开发一直是治疗传染病和癌症的重要方法。某些感染因子和癌细胞的高易错复制率可能会在相对较短的时间内导致耐药性。该项目将寻求一种开发不易出现靶点耐药性的酶抑制剂的新方法，即底物包膜假说，将开发和应用小分子配体的逆计算设计方法，并将通过与有机化学和药物化学专家的实验小组合作，在 HIV-1 蛋白酶的背景下广泛测试底物包膜假说，酶测定、蛋白质晶体学和病毒学。之所以选择 HIV 蛋白酶作为案例研究，是因为在临床化合物的选择压力下，在患者群体和细胞培养物中选择了有关耐药突变的大量先验信息。底物包膜假说认为，存在于底物共享体积内的抑制剂不易受到抗性突变的影响，因为此类突变体仍必须翻转底物。通过我们的计算方法，我们将开发对耐药突变体具有强大结合特性的 HIV 蛋白酶抑制剂，并通过协作工作对这些抑制剂进行合成、分析和表征。初步工作已证明取得了一些成功，并提出了有关底物包络假说的一些问题。拟议的项目涉及进一步发展我们的计算配体设计方法以实现当前工作的目标，但这些发展具有广泛的适用性，包括目标位点灵活性的有效处理、附加隐式溶剂能量函数形式的结合以及更有效的搜索算法的实施。拟议的项目将通过精细设计尊重和不尊重底物包膜的抑制剂来严格测试底物包膜假说，包括通过设计尊重包膜的变体来拯救屈服于抗性突变和破坏底物包膜的抑制剂。这些在其他方面相同的抑制剂的集合，但它们对底物包膜的粘附性不同，将成为将耐药谱与包膜假说联系起来的重要资源，我将与我的实验合作者一起研究这一点。拟议的项目还将设计和研究预计与一组抗性突变体的多个成员广泛结合的抑制剂的特性，并将它们与预计与单个靶点狭窄结合的抑制剂的特性进行比较。通过这种方式，可能会产生坚固粘合剂的新原理和对基质包络假说的改进。诸如底物包膜假设之类的隐式设计方法的一个特别优点是它们不需要事先明确了解耐药突变。公共卫生相关性：目前针对传染病和癌症的药物治疗受到耐药性出现的限制，以前有效的治疗通常通过靶点突变而失去效力。该项目旨在研究开发新疗法的方法，以预防或至少显着延迟耐药性的出现。初步工作将针对艾滋病毒蛋白酶，这是目前一些疗法的目标，但耐药菌株的出现仍然是一个重大问题。