Bioinformatics Division, ICMR-National Institute of Cancer Prevention and Research, Noida, India.
Phytochem Anal. 2018 Nov;29(6):559-568. doi: 10.1002/pca.2767. Epub 2018 Apr 18.
Natural products exhibit diverse scaffolds and are considered as suitable candidates for development of leads. However, poor pharmacokinetics often acts as a hindrance during the drug discovery process.
With a view of exploring the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of plant-based anticancer compounds, open-access databases (NPACT, CancerHSP and TaxKB) were analysed to identify molecules having properties favourable for drug ability.
Our workflow involved identification of molecules capable of passing each of the ADMET barriers based on physicochemical properties of molecules, and physiological barriers and factors.
The results revealed that out of 5086 phytomolecules, 63% were orally absorbable and 52% distributable. Also, an appreciable proportion of these compounds (45%) could be metabolised and excreted. Furthermore, 28% were found to be non-toxic for cardio toxicity and central nervous system (CNS) activity. Additionally, comparison against known anticancer drugs (reference dataset) revealed that the three libraries exhibit similar trends, thus providing additional confidence to the predictions. Overall, 28% of the molecular dataset was found to have suitable pharmacokinetic properties. We have also discussed a few natural products which exhibit favourable ADMET as well as low nano-micromolar in vitro anticancer activity.
We have created an interactive database (ADMETCan), which provides access to predicted ADMET of these anticancer phytomolecules. The ease of availability of this dataset is expected to minimise failure rate of these compounds and thus is expected to be beneficial to the scientific community involved in anticancer identification and development.
天然产物具有多样的结构骨架，被认为是开发先导化合物的合适候选物。然而，较差的药代动力学性质常常在药物发现过程中成为阻碍。
为了探索植物来源的抗癌化合物的吸收、分布、代谢、排泄和毒性（ADMET）特征，我们分析了开放获取数据库（NPACT、CancerHSP 和 TaxKB），以鉴定具有成药性有利特性的分子。
我们的工作流程包括根据分子的物理化学性质以及生理屏障和因素，识别能够通过每个 ADMET 屏障的分子。
结果表明，在 5086 种植物分子中，有 63%是口服可吸收的，52%是可分布的。此外，这些化合物中有相当一部分（45%）可以被代谢和排泄。此外，有 28%的化合物被发现对心脏毒性和中枢神经系统（CNS）活性无毒性。此外，与已知的抗癌药物（参考数据集）进行比较表明，这三个库具有相似的趋势，从而为预测提供了额外的可信度。总体而言，28%的分子数据集具有合适的药代动力学性质。我们还讨论了一些具有良好 ADMET 特性和低纳微米摩尔体外抗癌活性的天然产物。
我们创建了一个交互式数据库（ADMETCan），该数据库可提供这些抗癌植物分子的预测 ADMET 信息。该数据集易于获取，预计将降低这些化合物的失败率，从而使参与抗癌鉴定和开发的科学界受益。
