School of Life Sciences, Shaanxi Normal University, Xi'an 710062, China.
Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, Shaanxi Normal University, Xi'an 710062, China.
Int J Environ Res Public Health. 2021 Dec 16;18(24):13290. doi: 10.3390/ijerph182413290.
The -oxoguanine DNA glycosylase (OGG1) enzyme is a key DNA glycosylase mediating the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA molecule to the start base excision repair pathway. The OGG1 glycosylase function depletion has been seen to obstruct pathological conditions such as inflammation, A3 T-cell lymphoblastic acute leukemia growth, and neurodegenerative diseases, thus warranting OGG1 as an attractive anti-cancer enzyme. Herein, we employed several drug libraries intending to screen non-toxic inhibitory molecules against the active pocket of the enzyme that achieved stable binding mode in dynamics. Two anti-cancer compounds ([O-]C1=C(CC2=CC=CC=C2)SC(=[N+]1CC(=O)NC3=NC=C(CC4=CC=CC=C4)S3)S and CCCN(CCC)[S]-(=O)(=O)C1=CC=C(C=C1)C(=O)NNC2=NC3=CC=C(Br)C=C3C(=N2)C4=CC=CC=C4) from Selleckchem.com were identified to occupy the active pocket of OGG1 and bind with greater affinity than TH5487. The binding affinity of is -11.6 kcal/mol while that of is -10.7 kcal/mol in contrast to TH5487 (-9 kcal/mol). During molecular dynamic simulations versus time, the said compounds are tightly held by the enzyme with no minor structural deviations reported except flexible loops in particular those present at the N and C-terminal. Both the compounds produced extensive hydrophobic interactions with the enzyme along with stable hydrogen bonding. The docking and molecular dynamics simulations predictions were further validated by molecular mechanics with generalized Born and surface area solvation (MM/GBSA) and Poisson Boltzmann surface area (MM/PBSA), and WaterSwap binding energies that validated strong binding of the compounds to the enzyme. The MM/GBSA binding free energy for complex is -28.10 kcal/mol, complex is -50.14 kcal/mol) and is -46.91 kcal/mol while MM/PBSA value for , and is -23.38 kcal/mol, -35.29 kcal/mol and -38.20 kcal/mol, respectively. Computational pharmacokinetics support good druglike candidacy of the compounds with acceptable profile of pharmacokinetics and very little toxicity. All these findings support the notion that the compounds can be used in experiments to test their anti-cancer activities.
氧鸟嘌呤 DNA 糖基化酶（OGG1）是一种关键的 DNA 糖基化酶，介导从 DNA 分子中切除 7,8-二氢-8-氧鸟嘌呤（8-oxoG），进入起始碱基切除修复途径。OGG1 糖苷酶功能耗竭已被观察到会阻碍炎症、A3 T 细胞淋巴母细胞性白血病生长和神经退行性疾病等病理状况，因此，OGG1 被认为是一种有吸引力的抗癌酶。在此，我们使用了几种药物文库，旨在筛选针对酶活性口袋的非毒性抑制分子，这些分子在动力学中实现了稳定的结合模式。从 Selleckchem.com 中鉴定出两种抗癌化合物（[O-]C1=C(CC2=CC=CC=C2)SC(=[N+]1CC(=O)NC3=NC=C(CC4=CC=CC=C4)S3)S 和 CCCN(CCC)[S]-(=O)(=O)C1=CC=C(C=C1)C(=O)NNC2=NC3=CC=C(Br)C=C3C(=N2)C4=CC=CC=C4）占据了 OGG1 的活性口袋，并与 TH5487 相比具有更高的亲和力。化合物的结合亲和力分别为 -11.6 kcal/mol 和 -10.7 kcal/mol，而 TH5487 的结合亲和力为 -9 kcal/mol。在分子动力学模拟中，随着时间的推移，这些化合物被酶紧密地结合，除了特别存在于 N 和 C 末端的柔性环外，没有报告出较小的结构偏差。两种化合物都与酶产生了广泛的疏水相互作用，并具有稳定的氢键。对接和分子动力学模拟的预测进一步通过分子力学与广义 Born 和表面面积溶剂化（MM/GBSA）和泊松-玻尔兹曼表面面积（MM/PBSA）以及 WaterSwap 结合能进行验证，验证了化合物与酶的强结合。复合物的 MM/GBSA 结合自由能为 -28.10 kcal/mol，复合物的 MM/GBSA 结合自由能为 -50.14 kcal/mol），复合物的 MM/GBSA 结合自由能为 -46.91 kcal/mol，而 MM/PBSA 值分别为 -23.38 kcal/mol、-35.29 kcal/mol 和 -38.20 kcal/mol。计算药理学支持化合物具有良好的类药性，具有可接受的药代动力学特征和很小的毒性。所有这些发现都支持这样一种观点，即这些化合物可以在实验中用于测试它们的抗癌活性。
