Computational Design of Inhibitor Specificity

抑制剂特异性的计算设计

基本信息

批准号：
8059602
负责人：
BRUCE TIDOR
金额：
$ 21.51万
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 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059602
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。对于某些传染性剂和癌细胞的高容易错误复制率可以在相对较短的时间范围内导致耐药性。 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,酶测定，蛋白质晶体学和病毒学。由于在临床化合物的选择性压力下，在患者群体和细胞培养中选择的有关抗药性突变的大量信息，因此选择了HIV蛋白酶作为案例研究。底物包膜假设认为，驻留在底物共有的体积之内的抑制剂不易受到抗性突变，因为这种突变体必须将其移交给底物。通过我们的计算方法，我们将开发具有与抗性突变体面板具有鲁棒结合特性的HIV蛋白酶的抑制剂，并通过协作工作这些抑制剂将被合成，测定和表征。初步工作已经证明了一些成功，并提出了一些有关底物包膜假说的问题。拟议的项目涉及我们计算配体设计方法的进一步发展，以实现当前工作的目标，但是发展具有广泛的适用性，包括有效地处理目标位点灵活性，融合了其他隐性溶剂溶剂函数形式以及实施更有效的搜索算法。拟议的项目将通过抑制剂的精细规模设计来严格测试底物包膜假说，这些抑制剂的精细规模设计和不尊重底物包膜，包括挽救抑制阻力突变的抑制剂的测试，并通过尊重信封的变体设计，违反了抗性突变。这些原本相同的抑制剂在粘附于底物包膜上有所不同的集合将是将抗药性概况与信封假说联系起来的关键资源，我将与我的实验合作者一起研究。拟议的项目还将设计和研究预测将与抗电阻突变体的多个成员大致结合的抑制剂的性质，并将其与预测与单个目标结合的抑制剂的性质进行比较。这样，很可能会导致稳健粘合剂的新原则和对底物包络假设的改进。隐式设计方法（例如底物包络假设）的一个特殊优势是，它们不需要事先明确了解耐药性突变。公共卫生相关性：当前针对传染病和癌症的医学药物治疗受到抗药性的出现而受到限制，在这种情况下，以前有效的治疗通常会因靶标的突变而失去其有效性。该项目旨在研究开发新疗法的方法，以预防抗药性的出现或至少显着延迟。最初的工作将针对HIV蛋白酶，这是某些当前疗法的靶标，但抗性菌株的出现仍然是一个重要的问题。