Adnan Mohd, Jairajpuri Deeba Shamim, Chaddha Muskan, Khan Mohd Shahnawaz, Yadav Dharmendra Kumar, Mohammad Taj, Elasbali Abdelbaset Mohamed, Abu Al-Soud Waleed, Hussain Alharethi Salem, Hassan Md Imtaiyaz
Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia.
Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Bahrain.
J Pers Med. 2022 Jun 30;12(7):1083. doi: 10.3390/jpm12071083.
Oral squamous cell carcinoma (OSCC) is a major cause of death in developing countries because of high tobacco consumption. RAC-alpha serine-threonine kinase (AKT1) is considered as an attractive drug target because its prolonged activation and overexpression are associated with cancer progression and metastasis. In addition, several AKT1 inhibitors are being developed to control OSCC and other associated forms of cancers. We performed a screening of the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database to discover promising AKT1 inhibitors which pass through various important filters such as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, physicochemical properties, PAINS (pan-assay interference compounds) filters, PASS (prediction of activity spectra for substances) analysis, and specific interactions with AKT1. Molecules bearing admirable binding affinity and specificity towards AKT1 were selected for further analysis. Initially, we identified 30 natural compounds bearing appreciable affinity and specific interaction with AKT1. Finally, tuberosin and villosol were selected as potent and selective AKT1 inhibitors. To obtain deeper insights into binding mechanism and selectivity, we performed an all-atom molecular dynamics (MD) simulation and principal component analysis (PCA). We observed that both tuberosin and villosol strongly bind to AKT1, and their complexes were stable throughout the simulation trajectories. Our in-depth structure analysis suggested that tuberosin and villosol could be further exploited in the therapeutic targeting of OSCC and other cancers after further clinical validations.
口腔鳞状细胞癌（OSCC）是发展中国家主要的死亡原因之一，因为烟草消费量很高。RAC-α丝氨酸-苏氨酸激酶（AKT1）被认为是一个有吸引力的药物靶点，因为其持续激活和过表达与癌症进展和转移有关。此外，几种AKT1抑制剂正在研发中，以控制OSCC和其他相关形式的癌症。我们对IMPPAT（印度药用植物、植物化学与治疗学）数据库进行了筛选，以发现有前景的AKT1抑制剂，这些抑制剂需通过各种重要筛选，如ADMET（吸收、分布、代谢、排泄和毒性）特性、物理化学性质、PAINS（泛测定干扰化合物）筛选、PASS（物质活性谱预测）分析以及与AKT1的特异性相互作用。选择对AKT1具有良好结合亲和力和特异性的分子进行进一步分析。最初，我们鉴定出30种与AKT1具有可观亲和力和特异性相互作用的天然化合物。最后，选择了块茎素和绒毛醇作为有效的选择性AKT1抑制剂。为了更深入地了解结合机制和选择性，我们进行了全原子分子动力学（MD）模拟和主成分分析（PCA）。我们观察到块茎素和绒毛醇都能与AKT1强烈结合，并且它们的复合物在整个模拟轨迹中都很稳定。我们的深入结构分析表明，经过进一步临床验证后，块茎素和绒毛醇可进一步用于OSCC和其他癌症的治疗靶点研究。
