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Molecular modeling of Plasmodium falciparum peptide deformylase and structure-based pharmacophore screening for inhibitors

机译：恶性疟原虫肽脱晶体和基于结构的药物筛选抑制剂的分子模拟

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摘要

Plasmodium falciparum peptide deformylase (PfPDF), a metalloenzyme which catalytically removes the N-formyl group from N-terminal methionine from polypeptide during protein maturation, is a potential drug target for antimalarial drug design but is less explored in comparison to its bacterial counterpart due to difficulties in enzyme purification, the labile nature of the metal cofactors, and the absence of crystal data of the enzyme-inhibitor complex and inhibitors. We used molecular modeling techniques to study the effect of different metal ions, Co2+, Zn2+, Ni2+ and Fe2+ towards actinonin binding and recognized PfPDF-Co2+-actinonin inhibitor complex as the energetically favorable structure supported by biochemical characterizations. Further, we analyzed the favorable coordination geometry of bound metal cofactor and showed that its geometry did not affect the binding mode of actinonin consistent with the crystallographic observations which suggested that FlexX docking-based virtual screening may be effectively applied to recognize PfPDF binders. Structure-based pharmacophore screening of PfPDF-Co2+-actinonin complex recognized five potential hits and analyzed their effectiveness in chelating metal cofactor and ability to develop similar poses in both pharmacophore fit and docking. From the geometrical properties and characteristics of antibacterial PDF inhibitors, CAP01891052 (a triazine and quinoline containing molecule) and IBS297042 (an indole and piperidine containing molecule) were prioritized as promising lead molecules to modulate PfPDF activity.
机译：疟原虫肽脱色肽（PFPDF），蛋白质成熟期间催化从多肽中从N-末端甲硫氨酸中除去正甲酰基的金属酶，是抗疟药剂设计的潜在药物靶标，但与其细菌对应物相比，探索较低酶纯化的困难，金属辅因子的不稳定性，以及酶抑制剂复合物复合物的晶体数据的缺失。我们使用的分子建模技术研究了不同金属离子，CO2 +，Zn2 +，Ni2 +和Fe2 +对肌动蛋白结合的影响，并认识到PFPDF-CO2 + -Actinonin抑制剂复合物作为生物化学特征支持的能量良好结构。此外，我们分析了结合金属辅因子的有利协调几何形状，并表明其几何形状不影响actinonin的结合模式与结晶观察结果，这表明可以有效地应用于识别PFPDF粘合剂的FlexX对接的虚拟筛选。基于结构的PFPDF-CO2 + actinonin复合物的药效筛选公认的五个潜在的命中并分析了它们在螯合金属辅因子的效果以及在药仔佩特和对接中发育类似姿势的能力。从几何特性和抗菌PDF抑制剂的特征，CAP01891052（三嗪和喹啉的含分子）和IBS297042（吲哚和含分子哌啶）的优先作为有前途的先导分子以调节PfPDF活性。

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  • 来源
    《RSC Advances》 |2016年第35期|共20页
  • 作者

    Manhas Anu; Kumar Sivakumar Prasanth; Jha Prakash Chandra;

  • 作者单位

    Cent Univ Gujarat Sch Chem Sci Gandhinagar 382030 Gujarat India;

    Cent Univ Gujarat Sch Chem Sci Gandhinagar 382030 Gujarat India;

    Cent Univ Gujarat Sch Chem Sci Gandhinagar 382030 Gujarat India;

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  • 正文语种 eng
  • 中图分类 化学;
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