Bioinformatics and Biomedicals Research Group, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok 16424, West Java, Indonesia.
Molecules. 2021 Jan 13;26(2):375. doi: 10.3390/molecules26020375.
Epimutation by DNA Methyltransferase 1 (DNMT1), an epigenetic regulator enzyme, may lead to the proliferation of breast cancer. In this report, 168,686 natural products from the PubChem database were screened and modified by in silico method to acquire the potential inhibitor of DNMT1. The initial screening of PubChem natural products using Lipinski's and Veber's rules of three and toxic properties have resulted in 2601 fragment candidates. Four fragments from pharmacophore-based molecular docking simulation were modified by utilizing FragFP and the Lipinski's and Veber's rules of five, and resulted in 51,200 ligands. The toxicological screening collected 13,563 ligands for a series of pharmacophore-based molecular docking simulations to sort out the modified ligands, which had the better binding activity and interactions to DNMT1 compared to the standards, SAH, SAM, and SFG. This step resulted in five ligand candidates, namely C-7756, C-5769, C-1723, C-2129, and C-2140. The ADME-Tox properties prediction showed that the selected ligands are generally better than standards in terms of druglikeness, GI absorption, and oral bioavailability. C-7756 exhibited a stronger affinity to DNMT1 as well as better ADME-Tox properties compared to the other ligands.
DNA 甲基转移酶 1（DNMT1）的表观遗传调控酶的表观遗传调控可能导致乳腺癌的增殖。在本报告中，从 PubChem 数据库中筛选了 168686 种天然产物，并通过计算机方法进行修饰，以获得潜在的 DNMT1 抑制剂。使用 Lipinski 和 Veber 的三规则和毒性特性对 PubChem 天然产物进行初始筛选，得到 2601 个片段候选物。从基于药效团的分子对接模拟的四个片段中，通过利用 FragFP 和 Lipinski 和 Veber 的五规则进行修饰，并得到 51200 个配体。毒性筛选收集了 13563 个配体进行一系列基于药效团的分子对接模拟，以筛选出与标准品 SAH、SAM 和 SFG 相比具有更好的结合活性和相互作用的修饰配体。这一步得到了五个配体候选物，即 C-7756、C-5769、C-1723、C-2129 和 C-2140。ADME-Tox 性质预测表明，所选配体在类药性、GI 吸收和口服生物利用度方面通常优于标准品。与其他配体相比，C-7756 对 DNMT1 表现出更强的亲和力和更好的 ADME-Tox 性质。
