Peptide inhibitors of botulinum neurotoxin serotype A: Design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

KumarG.; KumaranD.; AhmedS.A.SwaminathanS.

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Peptide inhibitors of botulinum neurotoxin serotype A: Design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

机译：肉毒神经毒素肽抑制剂答:血清型设计、抑制cocrystal结构、结构与活性关系药效团模型

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Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC 50 of 0.9 μM and a K i of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

机译：肉毒杆菌神经毒素进行分类作为生物恐怖主义中心代理的类别疾病控制和预防中心(CDC)。肉毒杆菌的7种血清型(g)神经毒素,疾病的病原体肉毒中毒,阻止神经递质释放特别是裂开的三个陷阱(可溶性N-ethylmaleimide-sensitive因素附件蛋白受体)蛋白质和诱导弛缓性麻痹。药物设计方法中,肽抑制剂的设计及其抑制活动与肉毒杆菌血清型(肉毒毒素/)蛋白酶是确定。RRGF,抑制肉毒毒素/ IC 50的蛋白酶0.9μM和K我358海里。各种肽抑制剂的晶体结构在复杂的肉毒毒素/蛋白酶域也确定。活动和原子相互作用从cocrystal结构结构与活性关系进行了分析药效团模型发展。目前可用的模型,这药效团模型是基于酶抑制剂肽cocrystal结构和改善了现有模型,结合新的特性。

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《Acta crystallographica.Section D. Biological crystallography》 |2012年第5期|511-520|共10页
作者
KumarG.; KumaranD.; AhmedS.A.SwaminathanS.;
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作者单位

Department of Molecular Biology, Integrated Toxicology Division, US Army Medical Research Institute;

Biology Department, Brookhaven National Laboratory, Upton, NY 11973, United States;

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正文语种英语
中图分类化学;
关键词
Drug Receptors; Structure-Activity Relationship; atomic interactionsCenters for Disease Control and Prevention (U.S.)PeptidesSerotypebotulinum neurotoxinSoluble NSF Attachment Protein;

机译：药物受体;结构活性关系;原子interactionsCenters疾病控制和预防NSF附件蛋白质;

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Peptide inhibitors of botulinum neurotoxin serotype A: Design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

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