School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India; Nyro Research India, Kochi, Kerala, India.
Life Sci. 2020 Jun 1;250:117602. doi: 10.1016/j.lfs.2020.117602. Epub 2020 Mar 30.
Extrinsic ageing or photoageing relates to the onset of age-linked phenotypes such as skin hyperpigmentation due to UV exposure. UV induced upregulated production of tyrosinase enzyme, which catalyses the vital biochemical reactions of melanin synthesis is responsible for the inception of skin hyperpigmentation. We aimed to generate a validated QSAR model with a dataset consisting of 69 thio-semicarbazone derivatives to elucidate the physicochemical properties of compounds essential for tyrosinase inhibition and to identify novel lead molecules with enhanced tyrosinase inhibitory activity and bioavailability.
Lead optimization and insilico approaches were employed in this research work. QSAR model was generated and validated by exploiting Multiple Linear Regression method. Prioritization of lead-like compounds was accomplished by performing multi parameter optimization depleting molecular docking, bioavailability assessments and toxicity prediction for 69 compounds Derivatives of best lead compound were retrieved from chemical spaces.
Molecular descriptors explicated the significance of chemical properties essential for chelation of copper ions present in the active site of tyrosinase protein target. Further, derivatives which comprise of electron donating groups in their chemical structure were predicted and analysed for tyrosinase inhibitory activity by employing insilico methodologies including chemical space exploration.
Our research work resulted in the generation of a validated QSAR model with higher degree of external predictive ability and significance to tyrosinase inhibitory activity. We propose 11 novel derivative compounds with enhanced tyrosinase inhibitory activity and bioavailability.
外在老化或光老化与年龄相关表型的发生有关，如由于紫外线暴露引起的皮肤色素沉着。UV 诱导的酪氨酸酶酶的上调产生，该酶催化黑色素合成的重要生化反应，是皮肤色素沉着发生的原因。我们旨在利用包含 69 种硫代半卡巴腙衍生物的数据集生成一个经过验证的 QSAR 模型，以阐明对酪氨酸酶抑制至关重要的化合物的物理化学性质，并确定具有增强的酪氨酸酶抑制活性和生物利用度的新型先导分子。
在这项研究工作中采用了先导优化和计算方法。通过利用多元线性回归方法生成和验证了 QSAR 模型。通过进行多参数优化，包括分子对接、生物利用度评估和毒性预测，对 69 种化合物进行了优先级排序，以去除先导化合物。从化学空间中检索最佳先导化合物的衍生物。
分子描述符阐明了与存在于酪氨酸酶蛋白靶标活性部位的铜离子螯合的化学性质的重要性。此外，通过使用包括化学空间探索在内的计算方法学，对其化学结构中包含供电子基团的衍生物进行了酪氨酸酶抑制活性的预测和分析。
我们的研究工作产生了一个经过验证的 QSAR 模型，具有更高的外部预测能力和对酪氨酸酶抑制活性的重要意义。我们提出了 11 种具有增强的酪氨酸酶抑制活性和生物利用度的新型衍生物化合物。
