Heterochiral Dipeptides of Chimeric Cyclic Amino Acids

描述（由申请人提供）：本研究的目的是开发多种肽“构象模板”作为分子探针，即满足至少三个要求的相对刚性支架： (i)具有有限的3D结构（有限的明确的3D构象）; (ii)易于合成获得，并且 (iii)能够独特地定向肽侧链（α-β和β-γ键），所述肽侧链被认为在肽-受体相互作用期间传递大部分信息。 该提议提供了基于脯氨酸、氮杂脯氨酸、哌啶酸、氮杂哌啶酸、哌啶甲酸和异哌啶甲酸的嵌合氨基酸类似物的四环构象肽模板作为新的“特权支架”（嵌合氨基酸联合收割机结合了两种氨基酸的性质，一个实例是结合了D-和L-丙氨酸的空间性质的氨基异丁酸）。选择用于研究的配体是足够小的势能面可以通过DFT计算确定，和能量最小值和它们的相对能量评估。这为评估数据分析中要考虑的构象异构体的数量和相对能量提供了基础。将设计和合成新的化合物以引入共价约束，所述共价约束能够以最大的保真度对齐识别基序的氨基酸侧链，并且将通过分子建模的虚拟筛选来寻找与趋化因子受体的结合位点缺乏负空间相互作用。电化学助剂的新用途将允许在环状模板组装后连接侧链。开发特异性抑制的治疗靶点是CXCR 4受体，其具有作为抗病毒药物和肿瘤学的潜在应用。

DESCRIPTION (provided by applicant): The objective of this research is the development of a variety of peptide "conformational templates" as molecular probes, i.e. relatively rigid scaffolds that satisfy at least three requirements: (i) possess limited 3D structures (limited well-determined 3D conformers); (ii) be readily accessible synthetically, and (iii) able to uniquely orient the peptide side chains (both alpha-beta and beta-gamma bonds) that are believed to transfer most of the information during peptide-receptor interactions. This proposal offers tetracyclic conformational peptide templates based on chimeric amino acid analogs of proline, azaproline, pipecolic, azapipecolic, nipecotic and isonipecotic acids as novel "privileged scaffolds" (chimeric amino acids combine the properties of two amino acids, an example is aminoisobutyric acid that combines the steric properties of D- and L-alanine). The ligands chosen for study are sufficiently small that the potential energy surface can be determined by DFT calculations, and the energy minima and their relative energetics evaluated. This provide the basis for evaluating the number and relative energetics of conformers to be considered in data analysis. Novel compounds will be designed and synthesized to introduce covalent constraints that are able to align the amino-acid side chains of the recognition motif with greatest fidelity and lack of negative steric interaction with the binding site of chemokine receptors will be sought by virtual screening through molecular modeling. Novel uses of electrochemical auxiliaries will allow pendant side chains to be attached after the cyclic templates are assembled. The therapeutic target for development of specific inhibition is the CXCR4 receptor with potential applications as an antiviral and in oncology.