Novel and Effective Antifungal Compounds Derived from Molecular Field Analysis

描述（由申请人提供）：在美国和世界范围内，侵袭性真菌感染是一种日益常见和严重的疾病和死亡原因。白色念珠菌感染增加了十倍，比大肠杆菌和假单胞菌引起的疾病更频繁，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严重限制，寻找新药是真菌病研究的主要挑战。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。目前迫切需要能够有效对抗特定真菌种类的口服药物以及具有广谱抗真菌活性的化合物。对以前未开发的分子靶标显示出新的作用模式的化合物是非常可取的。在这里，我们使用一个专有的药物发现平台HarvestTM来鉴定一种已被证实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该靶点抑制剂，即天然产物soraphen A，但大规模生产的困难和可能的毒性问题阻碍了其作为药物治疗的使用。我们使用Harvest的分子建模技术对数据库中超过400万种化合物进行了计算筛选，并确定了那些最有可能与soraphen在同一位点结合的化合物。这些将根据它们与soraphen分子场模式的相似性进行排名，并过滤出表明成功抗感染的特征。所得到的化合物将在实验室获得并评估其对致病性真菌（如念珠菌）的活性和对目标酶的生化抑制作用。活性化合物将被滴定，可用的类似物的活性将被确认。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取/合成每个支架更有效的类似物。在第二阶段，预计1-3个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估。基于一系列广泛标准的最有效的化合物将进入临床前开发和临床试验阶段。公共卫生相关性：在美国和世界范围内，侵袭性真菌感染是一种日益常见和严重的疾病和死亡原因；例如，念珠菌已经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，用于鉴定已证实的抗真菌靶点的新抑制剂。利用已知抑制剂的分子场模式，在药物开发中显示出一些缺点，筛选商业上可获得的化合物数据库，并在体外对病原真菌进行检测，以找到有望克服这些缺点的化学先导物。

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.