Zafar Fahmina, Gupta Anjali, Thangavel Karthick, Khatana Kavita, Sani Ali Alhaji, Ghosal Anujit, Tandon Poonam, Nishat Nahid
Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India.
Division of Chemistry, School of Basic and Applied Science, Galgotias University, Greater Noida 201310, Uttar Pradesh, India.
ACS Omega. 2020 Mar 13;5(11):6021-6030. doi: 10.1021/acsomega.9b04398. eCollection 2020 Mar 24.
Anacardic acid (AA) and its derivatives are well-known for their therapeutic applications ranging from antitumor, antibacterial, antioxidant, anticancer, and so forth. However, their poor pharmacokinetic and safety properties create significant hurdles in the formulation of the final drug molecule. As a part of our endeavor to enhance the potential and exploration of the anticancer activities, a detailed study on the properties of selected AA derivatives was performed in this work. A comprehensive analysis of the drug-like properties of 100 naturally occurring AA derivatives was performed, and the results were compared with certain marketed anticancer drugs. The work focused on the understanding of the interplay among eight physicochemical properties. The relationships between the physicochemical properties, absorption, distribution, metabolism, and excretion attributes, and the in silico toxicity profile for the set of AA derivatives were established. The ligand efficacy of the finally scrutinized 17 AA derivatives on the basis of pharmacokinetic properties and toxicity parameters was further subjected to dock against the potential anticancer target cyclin-dependent kinase 2 (PDB ID: 1W98). In the docked complex, the ligand molecules (AA derivatives) selectively bind with the target residues, and a high binding affinity of the ligand molecules was ensured by the full fitness score using the SwissDock Web server. The BOILED-Egg model shows that out of 17 scrutinized molecules, 3 molecules exhibit gastrointestinal absorption capability and 14 molecules exhibit permeability through the blood-brain barrier penetration. The analysis can also provide some useful insights to chemists to modify the existing natural scaffolds in designing new anacardic anticancer drugs. The increased probability of success may lead to the identification of drug-like candidates with favorable safety profiles after further clinical evaluation.
漆树酸（AA）及其衍生物因其在抗肿瘤、抗菌、抗氧化、抗癌等方面的治疗应用而闻名。然而，它们较差的药代动力学和安全性特性在最终药物分子的制剂研发中造成了重大障碍。作为我们增强抗癌活性潜力和探索工作的一部分，本研究对选定的AA衍生物的特性进行了详细研究。对100种天然存在的AA衍生物的类药性质进行了全面分析，并将结果与某些市售抗癌药物进行了比较。这项工作着重于理解八种物理化学性质之间的相互作用。建立了AA衍生物组的物理化学性质、吸收、分布、代谢和排泄属性以及计算机模拟毒性概况之间的关系。基于药代动力学性质和毒性参数，最终筛选出的17种AA衍生物的配体效力进一步与潜在的抗癌靶点细胞周期蛋白依赖性激酶2（PDB ID：1W98）进行对接。在对接复合物中，配体分子（AA衍生物）与靶标残基选择性结合，并使用SwissDock网络服务器通过完全适应度评分确保配体分子具有高结合亲和力。“水煮蛋”模型显示，在17个经过筛选的分子中，有3个分子具有胃肠道吸收能力，14个分子具有穿过血脑屏障的渗透性。该分析还可以为化学家在设计新的漆树酸抗癌药物时修饰现有的天然骨架提供一些有用的见解。成功概率的增加可能会在进一步的临床评估后识别出具有良好安全性的类药候选物。
