Complex Systems Division, Beijing Computational Science Research Center, Beijing 100193, China.
College of Science and Mathematics, Rowan University, Glassboro, NJ 08028, USA.
Life Sci. 2024 Feb 1;338:122395. doi: 10.1016/j.lfs.2023.122395. Epub 2024 Jan 3.
Histone deacetylase 6 (HDAC6) contributes to cancer metastasis in several cancers, including triple-negative breast cancer (TNBC)-the most lethal form that lacks effective therapy. Although several efforts have been invested to develop selective HDAC6 inhibitors, none have been approved by the FDA. Toward this goal, existing computational studies used smaller compound libraries and shorter MD simulations. Here, we conducted a structure-based virtual screening of ZINC "Druglike" library containing 17,900,742 compounds using a Glide virtual screening protocol comprising various filters with increasing accuracy. The top 20 hits were subjected to molecular dynamics simulation, MM-GBSA binding energy calculations, and further ADMET prediction. Furthermore, enzyme inhibition assay and cell viability assay were performed on six available compounds from the identified hits. C4 (ZINC000077541942) with a good profile of predicted drug properties was found to inhibit HDAC6 (IC50: 4.7 ± 11.6 μM) with comparative affinity to that of the known HDAC6 selective inhibitor Tubacin (TA) in our experiments. C4 also demonstrated cytotoxic effects against triple-negative breast cancer (TNBC) cell line MDA-MB-231 with EC50 of 40.6 ± 12.7 μM comparable to that of TA (2-20 μM). Therefore, this compound, with pharmacophore features comprising a non-hydroxamic acid zinc-binding group, heteroaromatic linker, and cap group, is proposed as a novel HDAC6 inhibitor.
组蛋白去乙酰化酶 6(HDAC6)在多种癌症中促进癌症转移,包括三阴性乳腺癌(TNBC)-这是一种最致命的形式,缺乏有效的治疗方法。尽管已经投入了几项努力来开发选择性 HDAC6 抑制剂,但没有一种被 FDA 批准。针对这一目标,现有的计算研究使用了较小的化合物库和较短的 MD 模拟。在这里,我们使用包含 17900742 种化合物的 ZINC“可药用”库,根据不同的准确性,使用 Glide 虚拟筛选方案进行了基于结构的虚拟筛选,该方案包括各种过滤器。前 20 个命中物进行了分子动力学模拟、MM-GBSA 结合能计算,并进一步进行了 ADMET 预测。此外,还对从鉴定的命中物中获得的六种可用化合物进行了酶抑制测定和细胞活力测定。C4(ZINC000077541942)具有良好的预测药物特性,在我们的实验中,它被发现能够抑制 HDAC6(IC50:4.7±11.6μM),与已知的选择性 HDAC6 抑制剂 Tubacin(TA)具有可比性。C4 还对三阴性乳腺癌(TNBC)细胞系 MDA-MB-231 表现出细胞毒性作用,EC50 为 40.6±12.7μM,与 TA(2-20μM)相当。因此,这种化合物具有基于结构的虚拟筛选方案,包含非羟肟酸锌结合基团、杂芳环连接子和帽基团,被提议作为一种新型的 HDAC6 抑制剂。