Department of Pharmacy, BRAC University, Dhaka, Bangladesh.
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
J Biomol Struct Dyn. 2021 Oct;39(17):6467-6479. doi: 10.1080/07391102.2020.1802335. Epub 2020 Aug 4.
The overexpression of Akt1 (RAC-alpha serine/threonine-protein Kinase) and Akt2 (RAC-beta serine/threonine-protein Kinase) is a hallmark of Oral Squamous Cell Carcinoma (OSCC). Because of the elevated frequency of OSCC occurrence in South Asian countries, novel therapeutic approaches are indispensable. Drugs that inhibit the overexpression of Akt1 and Akt2 proteins in Akt pathway and do not cause reduced expression of MAOB can be leads for OSCC treatment. In this study, Akt1, Akt2 and MAOB were targeted and 100 CYP inhibitors were screened through several approaches and Galuteolin and Linarin were identified as potential leads for OSCC treatment as they inhibited Akt1 proteins with strong binding affinities of -12.3 and -11.5 kcal/mol respectively and also Akt2 proteins with strong binding affinities of -11.4 and -11.1 kcal/mol respectively, but they did not inhibit MAOB. Decreased expression of MAOB in tissues causes OSCC but overexpression is also responsible for other types of diseases and cancers. From the investigation of CYP inhibitors against MAOB, five CYP inhibitors- Diosmetin, Acacetin, Epicatechin, Eriodictyol and Capillin have expressed inhibitory action against MAOB without any interference with Akt1 and Akt2. This study mainly represents that Galuteolin and Linarin in the Akt pathway can be perceived for OSCC treatment and other five CYP inhibitors - Diosmetin, Acacetin, Epicatechin, Eriodictyol and Capillin for the treatment of other diseases and cancers caused by overexpression of MAOB. ADMET properties of CYP inhibitors obtained from admetSAR 2.0 and were compared with reference drugs for validation. Communicated by Ramaswamy H. Sarma.
Akt1（RAC-α丝氨酸/苏氨酸蛋白激酶）和 Akt2（RAC-β丝氨酸/苏氨酸蛋白激酶）的过表达是口腔鳞状细胞癌（OSCC）的标志。由于南亚国家 OSCC 的发病率较高，因此需要新的治疗方法。抑制 Akt 通路中 Akt1 和 Akt2 蛋白过表达而不会导致 MAOB 表达降低的药物可以成为 OSCC 治疗的先导。在这项研究中，针对 Akt1、Akt2 和 MAOB 进行了研究，并通过多种方法筛选了 100 种 CYP 抑制剂，发现白杨素和瑞香素是治疗 OSCC 的潜在先导化合物，因为它们分别以 -12.3 和 -11.5 kcal/mol 的强结合亲和力抑制 Akt1 蛋白，以及以 -11.4 和 -11.1 kcal/mol 的强结合亲和力抑制 Akt2 蛋白，但它们不抑制 MAOB。组织中 MAOB 的表达降低会导致 OSCC，但过表达也会导致其他类型的疾病和癌症。从 CYP 抑制剂对 MAOB 的研究中发现，五种 CYP 抑制剂-香豆素、芹菜素、儿茶素、圣草酚和毛蕊花糖苷对 MAOB 具有抑制作用，而不会干扰 Akt1 和 Akt2。这项研究主要表明，Akt 通路中的白杨素和瑞香素可用于治疗 OSCC，而其他五种 CYP 抑制剂-香豆素、芹菜素、儿茶素、圣草酚和毛蕊花糖苷可用于治疗因 MAOB 过表达引起的其他疾病和癌症。从 admetSAR 2.0 获得的 CYP 抑制剂的 ADMET 性质，并与参考药物进行了比较验证。由 Ramaswamy H. Sarma 传达。
