Department of Bioinformatics, Dow College of Biotechnology, Dow University of Health Sciences, Karachi, Pakistan.
Curr Cancer Drug Targets. 2019;19(11):906-918. doi: 10.2174/1568009619666190320102238.
Intestinal β-glucuronidase enzyme has a significant importance in colorectal carcinogenesis. Specific inhibition of the enzyme helps prevent immune reactivation of the glucuronide- carcinogens, thus protecting the intestine from ROS (Reactive Oxidative Species) mediatedcarcinogenesis.
Advancement in In-silico based techniques has provided a broad range of studies to carry out the drug design and development process smoothly using SwissADME and BOILED-Egg tools.
In our designed case study, we used SwissADME and BOILED-Egg predictive computational tools to estimate the physicochemical, human pharmacokinetics, drug-likeness, medicinal chemistry properties and membrane permeability characteristics of our recently In-vitro evaluated novel β-Glucuronidase inhibitors.
Out of the eleven screened potent inhibitors, compound (8) exhibited excellent bioavailability radar against the six molecular descriptors, good (ADME) Absorption, Distribution, Metabolism and Excretion along with P-glycoprotein, CYP450 isozymes and membranes permeability profile. On the basis of these factual observations, it is to be predicted that compound (8) can achieve in-vivo experimental clearance efficiently, Therefore, in the future, it can be a drug in the market to treat various disorders associated with the overexpression of β-Glucuronidase enzyme such as various types of cancer, particularly hormone-dependent cancer such as (breast, prostate, and colon cancer). Moreover, other compounds (1-7, & 9-11), have also shown good predictive pharmacokinetics, medicinal chemistry, BBB and HIA membranes permeability profiles with slight lead optimization to obtain improved results.
In consequence, in-silico based studies are considered to provide robustness for a rational drug design and development approach to avoid the possibility of failures of drug candidates in the later stages of drug development phases. The results of this study effectively reveal the possible attributes of potent β-Glucuronidase inhibitors, for further experimental evaluation.
肠道β-葡糖苷酸酶在结直肠癌发生中具有重要意义。该酶的特异性抑制有助于防止葡糖苷酸-致癌物的免疫再激活，从而保护肠道免受 ROS（活性氧化物种）介导的癌变。
基于计算机的技术进步为药物设计和开发过程提供了广泛的研究，使用 SwissADME 和 BOILED-Egg 工具可以顺利进行。
在我们设计的案例研究中，我们使用了 SwissADME 和 BOILED-Egg 预测性计算工具来评估我们最近在体外评估的新型β-葡糖苷酸酶抑制剂的物理化学、人体药代动力学、类药性、药物化学性质和膜通透性特征。
在筛选出的十一种有效抑制剂中，化合物 (8) 对六个分子描述符表现出极好的生物利用度雷达，具有良好的（ADME）吸收、分布、代谢和排泄特性，以及 P-糖蛋白、CYP450 同工酶和膜通透性特征。基于这些实际观察，预计化合物 (8) 可以有效地实现体内实验清除，因此，在未来，它可以成为一种市场上的药物，用于治疗与β-葡糖苷酸酶过度表达相关的各种疾病，如各种类型的癌症，特别是激素依赖性癌症，如（乳腺癌、前列腺癌和结肠癌）。此外，其他化合物（1-7 和 9-11）也表现出良好的预测药代动力学、药物化学、BBB 和 HIA 膜通透性特征，只需稍加优化即可获得更好的结果。
因此，基于计算机的研究被认为可以为合理的药物设计和开发方法提供稳健性，以避免候选药物在药物开发后期阶段失败的可能性。本研究的结果有效地揭示了潜在β-葡糖苷酸酶抑制剂的可能属性，以便进一步进行实验评估。
