Heterochiral Dipeptides of Chimeric Cyclic Amino Acids

超出所提供的空间。本研究的目的是开发各种肽“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（有限的确定的3D构象）；（ii）易于合成，（iii）能够独特地定位肽侧链（o_13和13- y键），这些侧链被认为在肽-受体相互作用期间传递大部分信息。这一建议提供了基于脯氨酸、管酸、nipecotic和异糖酸的嵌合氨基酸类似物的小三环和四环构象肽模板，作为新的“特权支架”（嵌合氨基酸结合了两种氨基酸的性质，例如结合了D-和l -丙氨酸的位阻性质的氨基异丁酸）。所选择的配体足够小，可以通过DFT计算确定势能面，并计算能量最小值及其相对能量。这将为评估数据分析中要考虑的构象的数量和相对能量学提供基础。新的化合物将被设计和合成，以引入共价约束，能够以最大的保真度排列识别基序的氨基酸侧链，并且将通过分子建模通过虚拟筛选寻求与整合素受体结合位点缺乏负空间相互作用的化合物。电化学助剂的新用途将允许在循环模板组装后附加垂坠侧链。发展特异性抑制的治疗靶点是o_4137整合素受体。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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 sidechains (both o_-13and 13--ybonds) that are believed to transfer most of the information during peptide-receptor interactions. This proposal offers small tri- and tetracyclic conformational peptide templates based on chimeric amino acid analogs of proline, pipecolic, 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 will 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 sidechains of the recognition motif with greatest fidelity and lack of negative steric interaction with the binding site of integrin receptors will be sought by virtual screening through molecular modeling. Novel uses of electrochemical auxiliaries will allow pendant sidechains to be attached after the cyclic templates are assembled. The therapeutic target targeted for development of specific inhibition is the o_4137integrin receptor. PERFORMANCE SITE ========================================Section End===========================================