Novel and Effective Antifungal Compounds Derived from Molecular Field Analysis

描述(申请人提供)：侵袭性真菌感染在美国和世界范围内是一种日益常见和严重的疾病和死亡原因。白色念珠菌的感染已经增加了十倍，变得比大肠杆菌和假单胞菌引起的疾病更频繁，它已经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很大限制，寻找新药是真菌疾病研究的主要挑战。目前可用的治疗方法有很大的缺点，包括严重的副作用和出现病原体抗药性。非常需要新的口服给药，对特定真菌种类有效，以及显示广谱抗真菌活性的化合物。展示一种针对以前未开发的分子靶标的新作用模式的化合物是非常可取的。在这里，我们应用专利药物发现平台HarvestTM来识别已被证实的抗真菌靶点--乙酰辅酶A羧基酶(ACCase)的抑制剂。目前存在这一靶点的一种有效的抑制剂，即天然产品索拉芬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。我们已经使用嘉实的分子建模技术对超过400万种化合物的数据库进行了计算机筛选，并确定了那些最有可能与山梨醇结合在同一位置的化合物。这些药物将根据它们与索拉芬分子场模式的相似性进行排序，并筛选出指示成功抗感染的特征。所得到的化合物将在实验室获得并评估对致病真菌(如念珠菌)的活性和对目标酶的生化抑制。活性化合物将被滴定，可用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为每个支架获取/合成更有效的类似物。在第二阶段，预计将优先考虑1-3个化学支架，并将其转移到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。根据广泛的标准，最有效的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是一个专利药物发现平台，用于识别已证实的抗真菌靶点的新抑制剂。利用一种已知的抑制剂的分子场模式，对商业可用化合物数据库进行筛选，并在体外对病原真菌进行检测，以找到预计可以克服这些缺点的化学线索。

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.