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新型恶性疟原虫半胱氨酸蛋白酶 falcipain-2 杂合内酯-查尔酮和色胺-查尔酮抑制剂的虚拟设计，探索 S2 活性位点口袋。

Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone-chalcone and isatin-chalcone inhibitors probing the S2 active site pocket.

机构信息

a Laboratoire de Physique Fondamentale et Appliquée (LPFA) , University of Abobo Adjamé (now Nangui Abrogoua) , Abidjan , Côte d'Ivoire.

b Laboratoire de Chimie Organique Structurale et Théorique , University of Cocody (now Felix Houphouët Boigny) , Abidjan , Côte d'Ivoire.

出版信息

J Enzyme Inhib Med Chem. 2019 Dec;34(1):547-561. doi: 10.1080/14756366.2018.1564288.

DOI:10.1080/14756366.2018.1564288
PMID:30696325
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6352947/
Abstract

We report computer-aided design of new lactone-chalcone and isatin-chalcone (HLCIC) inhibitors of the falcipain-2 (PfFP-2). 3D models of 15 FP-2:HLCIC1-15 complexes with known observed activity (IC) were prepared to establish a quantitative structure-activity (QSAR) model and linear correlation between relative Gibbs free energy of enzyme:inhibitor complex formation (ΔΔG) and IC: pIC = -0.0236 × ΔΔG+5.082(#); R = 0.93. A 3D pharmacophore model (PH4) derived from the QSAR directed our effort to design novel HLCIC analogues. During the design, an initial virtual library of 2621440 HLCIC was focused down to 18288 drug-like compounds and finally, PH4 screened to identify 81 promising compounds. Thirty-three others were added from an intuitive substitution approach intended to fill better the enzyme S2 pocket. One hundred and fourteen theoretical IC (IC values were predicted by means of (#) and their pharmacokinetics (ADME) profiles. More than 30 putative HLCICs display IC 100 times superior to that of the published most active training set inhibitor HLCIC1.

摘要

我们报告了计算机辅助设计的新内酯查耳酮和色胺查耳酮（HLCIC）的疟原虫蛋白酶-2（PfFP-2）抑制剂。制备了 15 个 FP-2：HLCIC1-15 复合物的 3D 模型，这些复合物具有已知的观察到的活性（IC），以建立定量构效关系（QSAR）模型和酶：抑制剂复合物形成的相对吉布斯自由能（ΔΔG）与 IC：pIC 的线性相关性（IC：pIC = -0.0236 × ΔΔG + 5.082）（#）；R = 0.93。从 QSAR 衍生的 3D 药效团模型（PH4）指导我们设计新型 HLCIC 类似物。在设计过程中，最初的 HLCIC 虚拟库 2621440 个化合物被聚焦到 18288 个类似物上，最后通过 PH4 筛选出 81 个有前途的化合物。另有 33 个化合物是通过直观的取代方法添加的，旨在更好地填充酶 S2 口袋。有 114 种理论上的 IC（通过（#）预测的 IC 值）及其药代动力学（ADME）特征。超过 30 种假定的 HLCIC 的 IC 比已发表的最活跃的训练集抑制剂 HLCIC1 高 100 倍。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/1ce5969ca115/IENZ_A_1564288_F0012_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/30fa3937b460/IENZ_A_1564288_F0009_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/1ce5969ca115/IENZ_A_1564288_F0012_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/88a6e44df358/IENZ_A_1564288_F0001_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/1e62706fd1d4/IENZ_A_1564288_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/512604b5dbf4/IENZ_A_1564288_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/3210408ba737/IENZ_A_1564288_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/d53289aaf500/IENZ_A_1564288_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/7a8e2290d798/IENZ_A_1564288_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/5a23fe0742e7/IENZ_A_1564288_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/30fa3937b460/IENZ_A_1564288_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/873cf5257e5e/IENZ_A_1564288_F0010_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/f1bcd2dc6dec/IENZ_A_1564288_F0011_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/67c7/6352947/1ce5969ca115/IENZ_A_1564288_F0012_C.jpg

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Virtually Designed Triclosan-Based Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis and of Plasmodium falciparum.
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Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2.导向性药物再利用：恶性疟原虫蛋白酶-2新型竞争性和非竞争性抑制剂的发现
Front Chem. 2019 Aug 6;7:534. doi: 10.3389/fchem.2019.00534. eCollection 2019.
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