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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：
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感染性疾病和癌症的基本方法。某些感染因子和癌细胞的高易错复制率可能在相对较短的时间尺度上导致耐药性。该项目将寻求一种新的方法来开发酶抑制剂，这种酶抑制剂不太容易出现靶标耐药性，即底物包膜假设，将开发和应用小分子配体的逆向计算设计方法，并将通过与有机和药物化学方面的实验小组专家的合作，在HIV-1蛋白酶的背景下广泛测试底物包膜假设，酶分析、蛋白质晶体学和病毒学。HIV蛋白酶已被选为案例研究，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大量关于耐药突变的先前信息。底物包膜假说认为，存在于底物共享体积内的抑制剂对耐药突变不太敏感，因为这些突变体仍然必须转换底物。通过我们的计算方法，我们将开发HIV蛋白酶抑制剂，其对抗性突变体具有强大的结合特性，并且通过合作工作，这些抑制剂将被合成，分析和表征。初步工作已经取得了一些成功，并提出了一些问题，关于基板信封假说。拟议的项目涉及我们的计算配体设计方法的进一步发展，以实现当前工作的目标，但发展具有广泛的适用性，包括有效的治疗目标网站的灵活性，纳入额外的隐式溶剂能量函数的形式，和更有效的搜索算法的实施。拟议项目将通过对遵循和不遵循底物包膜的抑制剂进行精细设计，严格检验底物包膜假设，包括通过设计遵循包膜的变体，对屈服于耐药突变和违反底物包膜的抑制剂进行拯救试验。这些在其他方面相同的抑制剂的集合在它们对底物包膜的粘附性方面不同，这将是将耐药谱与包膜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，并将其与预测与单一靶标狭窄结合的抑制剂的特性进行比较。通过这种方式，可能会产生用于稳健粘合剂的新原理和对基质包络假设的改进。隐式设计方法（如底物包膜假设）的一个特别优点是它们不需要事先明确了解耐药突变。公共卫生关系：目前用于感染性疾病和癌症的医学药物治疗受到耐药性出现的限制，其中先前有效的治疗通常通过靶点突变而失去有效性。该项目旨在研究开发新疗法的方法，以防止或至少显着延迟耐药性的出现。最初的工作将针对HIV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。