基于吡唑的GGT1高效抑制剂：合成，生物学评估和分子对接研究,European Journal of Medicinal Chemistry

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基于吡唑的GGT1高效抑制剂：合成，生物学评估和分子对接研究
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2016-09-11 11:10:38
Muhammad Mansha, Udayappan Udhaya Kumari, Zoe Cournia, Nisar Ullah

在这项研究中，已合成了一系列基于吡唑的GGTI-DU40（1）的结构类似物，并对其对香叶基香叶基转移酶1（GGT1）和法尼基转移酶（FT）的抑制作用进行了生物学评估。筛选结果显示2（IC ₅₀ = 2.4μM ）和5（IC ₅₀ = 3.1μM）是有效的GGT1抑制剂（GGTIs），与对照化合物1（IC ₅₀ = 3.3μM）相比，具有更高的抑制活性。进一步测定了这些化合物对MDA-MB-231细胞的抗增殖功效，表明其活性2（IC ₅₀ = 7.6μM）明显高于1（IC ₅₀= 23.0μM）。为了检查完整化合物在完整细胞中抑制GGT1的能力，对MDA-MB-231细胞系进行了蛋白质印迹分析，发现其具有极高的2和5抑制细胞活性，并证明了它们抑制NPG1异戊二烯化的能力。内源性蛋白质。分子对接研究2对与香叶基香叶基焦磷酸酯（GGPP）类似物和KKKSKSKTKCVIL肽底物的CaaX（C =半胱氨酸，aa =脂肪族氨基酸和X =任何氨基酸）部分复合的GGT1的晶体结构进行的对接研究2和GGT1的结合口袋之间的键相互作用和π-π接触。这些数据一起表明化合物2可进行体内研究以进一步评估其功效和细胞毒性。

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Pyrazole-based potent inhibitors of GGT1: Synthesis, biological evaluation, and molecular docking studies

In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC₅₀ = 2.4 μM) and 5 (IC₅₀ = 3.1 μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC₅₀ = 3.3 μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231 cells which indicated a significantly higher activity of 2 (IC₅₀ = 7.6 μM) compared to 1 (IC₅₀ = 23.0 μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231 cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C = cysteine, aa = aliphatic amino acids, and X = any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in vivo investigation to further assess its efficacy and cytotoxicity.

更新日期：2016-09-12

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