Novel and Effective Antifungal Compounds Derived from Molecular Field Analysis

分子场分析衍生的新型有效抗真菌化合物

• 批准号: 7536872
• 负责人: Matthew W Dimmic
• 金额: $ 10.86万
• 依托单位: DIVERGENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536872
• 关键词: Accounting; Acetyl-CoA Carboxylase; Adverse effects; Animal Model; Animals; Anti-Infective Agents; Antifungal Agents; Aspergillus; Binding; Biochemical; Biological; Biological Assay; Biological Factors; Candida; Candida albicans; Cessation of life; Characteristics; Chemical Structure; Chemicals; Chemistry; Clinical Management; Clinical Trials; Cultured Cells; Databases; Development; Disease; Drug Controls; Drug Formulations; Drug Kinetics; Electrophoretic Mobility Shift Assay; Enzymes; Escherichia coli; Exhibits; Fluorescence Spectroscopy; Future; Goals; Harvest; Human; In Vitro; Industrial fungicide; Infection; Invasive; Investigation; Laboratories; Lead; Methods; Modeling; Molecular; Molecular Target; Mycoses; Numbers; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Predisposition; Property; Pseudomonas; Public Health; Publishing; Research; Research Design; Research Proposals; Resistance; Screening Result; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Technology; Testing; Toxic effect; Toxicology; United States; Validation; analog; base; desire; drug development; drug discovery; evaluation/testing; experience; fungus; in vitro Assay; inhibitor/antagonist; molecular modeling; novel; pathogen; pre-clinical; prevent; scaffold; scale up; soraphen A; success

DESCRIPTION (provided by applicant): Invasive fungal infections are an increasingly common and serious cause of illness and death in the U.S. and worldwide. Infection by Candida albicans has increased tenfold to become more frequent than diseases caused by E. coli and Pseudomonas, and it has become one of the most common fatal infections in the United States. Clinical management of invasive fungal infections is significantly constrained, and the search for new drugs represents a major challenge to mycotic disease research. Currently available treatments have significant drawbacks, including serious side effects and the emergence of pathogen resistance. There is a significant need for new orally-deliverable drugs effective against specific fungal species as well as compounds exhibiting broad-spectrum antifungal activity. Compounds demonstrating a novel mode of action against previously untapped molecular targets are highly desirable. Here we apply HarvestTM, a proprietary drug discovery platform, to identify inhibitors of a proven antifungal target, acetyl-CoA carboxylase (ACCase). A potent inhibitor of this target currently exists, the natural product soraphen A, but difficulty in large-scale manufacture and possible toxicity concerns have prevented its use as a pharmaceutical treatment. We have used Harvest's molecular modeling technology to computationally screen a database of over four million compounds and identify those most likely to bind at the same site as soraphen. These will be ranked based on their similarity to soraphen's molecular field pattern and filtered for characteristics indicative of successful anti-infectives. The resulting compounds will be acquired and evaluated in the laboratory for activity against pathogenic fungi such as Candida and for biochemical inhibition of the target enzyme. Active compounds will be titrated and the activity of available analogs will be confirmed. It is anticipated that 20-50 active compounds will result from these screens, facilitating further model refinements and the acquisition/synthesis of more efficacious analogs for each scaffold. During Phase II, it is anticipated that 1-3 chemical scaffolds will be prioritized and moved into spectrum testing against additional fungal species, preliminary toxicology testing, and evaluation in animal models. The most effective compounds based on a broad set of criteria would then advance into pre-clinical development and clinical trials. PUBLIC HEALTH RELEVANCE: Invasive fungal infections are an increasingly common and serious cause of illness and death in the U.S. and worldwide; for example, Candida has become one of the most common fatal pathogens in the United States. HarvestTM, a proprietary drug discovery platform, is applied to identify novel inhibitors of a proven antifungal target. Using the molecular field pattern of a known inhibitor that exhibits some drawbacks for drug development, a database of commercially available compounds is screened and assayed in vitro against pathogenic fungi to find chemical leads which are predicted to overcome these drawbacks.

描述（由申请人提供）：侵袭性真菌感染是美国和世界范围内日益常见和严重的疾病和死亡原因。白色念珠菌的感染比大肠杆菌引起的疾病增加了十倍。大肠杆菌和假单胞菌，它已成为美国最常见的致命感染之一。侵袭性真菌感染的临床管理受到显着限制，新药的寻找对真菌病研究构成了重大挑战。目前可用的治疗方法有明显的缺点，包括严重的副作用和病原体耐药性的出现。对有效对抗特定真菌物种的新的可口服递送的药物以及表现出广谱抗真菌活性的化合物存在显著需求。显示出针对先前未开发的分子靶标的新作用模式的化合物是高度期望的。在这里，我们应用HarvestTM，一个专有的药物发现平台，以确定一个被证明的抗真菌靶点，乙酰辅酶A羧化酶（ACCase）的抑制剂。目前存在一种有效的抑制剂，天然产物索拉芬A，但大规模生产的困难和可能的毒性问题阻止了其作为药物治疗的用途。我们已经使用Harvest的分子建模技术来计算筛选超过400万种化合物的数据库，并确定那些最有可能与索拉芬结合在同一位点的化合物。这些将根据其与索拉芬分子场模式的相似性进行排名，并筛选出成功抗感染药物的特征。将获得所得化合物，并在实验室中评价其对致病真菌（如念珠菌）的活性和对靶酶的生化抑制作用。将滴定活性化合物，并确认可用类似物的活性。预计这些筛选将产生20 - 50种活性化合物，促进进一步的模型改进和获得/合成每种支架的更有效的类似物。在第二阶段，预计1 - 3种化学支架将被优先考虑，并进入针对其他真菌物种的光谱测试、初步毒理学测试和动物模型评价。然后，基于一系列广泛标准的最有效化合物将进入临床前开发和临床试验。公共卫生相关性：侵袭性真菌感染是美国和世界范围内日益常见和严重的疾病和死亡原因;例如，念珠菌已成为美国最常见的致命病原体之一。HarvestTM是一个专有的药物发现平台，用于识别已证实的抗真菌靶点的新型抑制剂。使用已知的抑制剂的分子场模式，表现出药物开发的一些缺点，商业上可获得的化合物的数据库进行筛选，并在体外对致病真菌进行测定，以找到预测克服这些缺点的化学线索。