Novel inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR)

1-脱氧-D-木酮糖-5-磷酸还原异构酶 (DXR) 的新型抑制剂

基本信息

批准号：
7989076
负责人：
Yongcheng Song
金额：
$ 23.03万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-18 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989076
关键词：
Anabolism Animals Anti-Bacterial Agents Anti-Infective Agents Antimalarials Bacillus anthracis Bacteria Bacterial Infections Binding Biological Cessation of life Clinical Trials Communicable Diseases Complex D-xylulose-5-phosphate Development Diphosphates Docking Drug Design Drug Kinetics Drug resistance Enterococcus faecalis Enzymes Escherichia coli Goals Gram-Negative Bacteria Gram-Positive Bacteria Haemophilus influenzae Half-Life Human Human Cell Line In Vitro Isoprene Klebsiella pneumonia bacterium Lead Libraries Malaria Micrococcus luteus Mycobacterium tuberculosis Organism Parasites Parasitic Diseases Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Plasmodium falciparum Property Pseudomonas aeruginosa Quantitative Structure-Activity Relationship Recombinants Research Resistance Series Structure Testing Therapeutic Time Toxic effect Toxoplasma gondii Work base cytotoxicity test design drug discovery fosmidomycin improved in vitro testing inhibitor/antagonist inorganic phosphate isopentenyl pyrophosphate isoprenoid killings mevalonate non-drug novel pathogen pathogenic bacteria public health relevance scaffold small molecule

项目摘要

DESCRIPTION (provided by applicant): The overall objectives of this proposal are to use a combination of traditional medicinal chemistry and computational, structure based drug design to develop novel small molecule inhibitors of 1-deoxy-D-xylulose-5- phosphate reductoisomerase (DXR) and test their in vitro biological activities on pathogenic bacteria and parasites. Isoprene biosynthesis is essential to all organisms. Humans use the mevalonate pathway to produce isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), two common precursors for all isoprenoid biosynthesis; however, in most pathogenic bacteria, such as P. aeruginosa and M. tuberculosis, as well as apicomplexan parasites, such as P. falciparum and T. gondii, the non-mevalonate pathway is used to make IPP and DMAPP. Since humans lack all the 7 enzymes in the non-mevalonate pathway, it has become an attractive target for anti-infective drug discovery. Fosmidomycin has been found to be the only potent inhibitor of this pathway, blocking DXR, the 2nd enzyme, and has antibacterial activity against many Gram- negative bacteria and antimalarial activity in recent clinical trials. However, Gram-positive bacteria (e.g., M. tuberculosis) and some Gram-negative bacteria as well as certain pathogenic parasites (e.g., T. gondii) are resistant to fosmidomycin. In addition, it has a poor pharmacokinetic profile with a half-life in plasma of 0.5-1.5 h. Given the current devastating situation facing quickly rising drug resistance as well as shortage of new anti- infective drugs, there is a pressing need to find new weaponry for infectious diseases. The first Specific Aim is to use a combination of medicinal chemistry and computational, structure based drug design to develop novel inhibitors of DXR. Based on rational, structure based design, we have found novel, drug-like lead inhibitors with Kis as low as 310 nM against a recombinant E. coli DXR enzyme. Our docking studies showed that they could bind to DXR in different modes from that of fosmidomycin. These drug-like compounds should have great potential for further development. We propose 1) to use medicinal chemistry to make several series of compound libraries based on the scaffolds of the lead inhibitors, in order to find compounds with improved activity; 2) to carry out QSAR studies of these compounds; 3) to obtain x-ray crystal structures of DXR in complex with our novel inhibitors; and 4) to use the results from the computational and crystallographic studies to guide our further drug design and synthesis. The second Specific Aim is to test in vitro biological activity of our inhibitors on a broad range of bacteria and apicomplexan parasites as well as their recombinant DXR enzymes. Finally, we will also test the cytotoxicity of our potent DXR inhibitors on human cell lines to evaluate their potential toxicity. PUBLIC HEALTH RELEVANCE: The research proposed is designed to lead to new potential therapeutics to treat drug-resistant infectious diseases. We will focus on the discovery and development of novel compounds that block essential biological targets that are exclusively found in bacteria and malaria parasites.

描述（由申请人提供）：该提案的总体目标是结合传统的药物化学和基于结构的药物设计的组合来开发一种新型的小分子抑制剂，该小分子抑制剂的1-脱氧糖 - 5-磷酸磷酸盐还原酶（DXR）（DXR）并测试其对病理性细菌剂和帕氏疗法的体外生物学活性。异戊二烯生物合成对所有生物都是必不可少的。人类使用甲戊酸途径来产生异戊烯基二磷酸（IPP）和二甲基二磷酸二磷酸（DMAPP），这是所有类异跨生物合成的两个常见前体；然而，在大多数致病性细菌中，例如铜绿假单胞菌和结核分枝杆菌，以及丙花寄生虫，例如恶性疟原虫和gondii，非甲磺酸盐途径用于使IPP和DMAPP进行IPP和DMAPP。由于人类缺乏非甲状腺素途径中的所有7种酶，因此它已成为抗感染药物发现的有吸引力的靶标。已发现fosmidomycin是该途径的唯一有效抑制剂，阻断了DXR，第二酶，并且在最近的临床试验中具有针对许多革兰氏阴性细菌和抗菌活性的抗菌活性。然而，革兰氏阳性细菌（例如，结核杆菌）和一些革兰氏阴性菌以及某些致病寄生虫（例如T. Gondii）对fosmidymycin具有抗性。此外，它的药代动力学特征较差，血浆中的半衰期为0.5-1.5 h。鉴于目前遭受抗药性迅速增加以及新的抗感染性药物的灾难性局势，因此需要寻找用于传染病的新武器的迫切需求。第一个具体目的是将药物化学和基于计算，结构的药物设计的组合来开发DXR的新型抑制剂。基于基于理性的结构设计，我们发现针对重组大肠杆菌DXR酶，具有KIS的新型药物样铅抑制剂低至310 nm。我们的对接研究表明，它们可以与fosmidomycin的不同模式结合DXR。这些类似药物的化合物应该具有进一步发展的巨大潜力。我们建议1）使用药物化学基于铅抑制剂的支架制作几个系列化合物文库，以找到具有改善活性的化合物； 2）对这些化合物进行QSAR研究； 3）获得与我们的新型抑制剂复合物中DXR的X射线晶体结构； 4）使用计算和晶体学研究的结果来指导我们的进一步药物设计和合成。第二个具体目的是测试我们抑制剂在广泛的细菌和Apicomplexan寄生虫及其重组DXR酶上的体外生物学活性。最后，我们还将测试人类细胞系上有效DXR抑制剂的细胞毒性，以评估其潜在的毒性。公共卫生相关性：提出的研究旨在导致新的潜在治疗药物治疗耐药性感染疾病。我们将重点关注新型化合物的发现和开发，这些化合物阻止了细菌和疟原虫寄生虫中仅发现的基本生物学靶标。