Department of Organic Synthesis, Institute of the Chemistry of Plant Substances, Tashkent, Uzbekistan.
Bioorg Med Chem. 2010 Jun 15;18(12):4300-9. doi: 10.1016/j.bmc.2010.04.090. Epub 2010 May 20.
This study presents a simple method to design an active peptide based on a description of the structural preferences of peptide via its peptide fragments. In a previous design, while searching for lead peptide candidates, the efficacy of a design approach that was based on the use of a cyclic peptide as a model of linear analog was demonstrated. Analysis of the conformational behavior of the peptide models showed that an analogical approach could be applied in order to assess the conformational space that was occupied by a peptide by using peptide fragments. In order to assess the proposed method, a design of a competitive inhibitor for HMG-CoA reductase (HMGR) was performed. Two starting points were used in the design: (1) determined recognized residues and (2) the structural preference of a peptide, such as a beta-turn conformation in the present design. Two sets of peptides were developed based on the different location of a beta-turn structure relative to a recognized residue. Set 1 contains peptides in which a recognized residue is included in turn conformation. In Set 2, the turn structure is located distantly from the recognized residues. The design parameter 'V' that was applied in previous studies was slightly modified for the purpose of the current research. The 17 previously and 8 newly designed peptides were estimated by this parameter. In each set, one sequence was selected as a lead peptide candidate for each set: GF(4-fluoro)PEGG for Set 1 and DFGYVAE for Set 2. The inhibitory activities improved in each set. The IC(50) for the GF(4-fluoro)PEGG peptide was found to be 0.75 microM, while the linear DFGYVAE peptide (IC(50)=0.16 microM) showed a 3000-fold increase in inhibitory activity compared to the first isolated LPYP peptide (IC(50)=484 microM) from soybeans. The comparison of the structure-activity relationship (SAR) data between Set 1 and 2 provided an opportunity to design the peptides in terms of peptide selectivity. A structural analysis of the modeled peptides confirmed the appropriateness of the proposed method for the design of active peptides.
本研究提出了一种基于描述肽的结构偏好的简单方法，通过其肽片段来设计活性肽。在以前的设计中，在寻找先导肽候选物时，证明了基于使用环状肽作为线性类似物模型的设计方法的有效性。对肽模型的构象行为进行分析表明，类似的方法可以应用于通过使用肽片段来评估肽占据的构象空间。为了评估所提出的方法，设计了 HMG-CoA 还原酶 (HMGR) 的竞争性抑制剂。在设计中使用了两个起点：（1）确定的识别残基和（2）肽的结构偏好，例如在本设计中的β-转角构象。基于β-转角结构相对于识别残基的不同位置，开发了两组肽。第 1 组包含包含在转角构象中的识别残基的肽。在第 2 组中，转角结构远离识别残基。在以前的研究中应用的设计参数'V'在本次研究中略作修改。应用此参数对以前研究中的 17 个肽和新设计的 8 个肽进行了估计。在每组中，为每组选择一个序列作为先导肽候选物：第 1 组中的 GF(4-氟)PEGG 和第 2 组中的 DFGYVAE。每组的抑制活性均有所提高。发现 GF(4-氟)PEGG 肽的 IC(50)为 0.75μM，而线性 DFGYVAE 肽（IC(50)=0.16μM）的抑制活性比从大豆中首次分离的 LPYP 肽（IC(50)=484μM）提高了 3000 倍。第 1 组和第 2 组之间的结构-活性关系（SAR）数据的比较提供了一个机会，可以根据肽的选择性来设计肽。对模型肽的结构分析证实了该方法适用于设计活性肽。
