Laboratory of Innovative Technologies, National School of Applied Sciences of Tangier, Abdelmalek Essaadi University, Tetouan, Morocco.
ProteinInsights, New Delhi, India.
J Biomol Struct Dyn. 2024 Feb-Mar;42(4):1629-1646. doi: 10.1080/07391102.2023.2209650. Epub 2023 May 18.
Coumarins are a highly privileged scaffold in medicinal chemistry. It is present in many natural products and is reported to display various pharmacological properties. A large plethora of compounds based on the coumarin ring system have been synthesized and were found to possess biological activities such as anticonvulsant, antiviral, anti-inflammatory, antibacterial, antioxidant as well as neuroprotective properties. Despite the wide activity spectrum of coumarins, its naturally occurring derivatives are yet to be investigated in detail. In the current study, a chemical library was created to assemble all chemical information related to naturally occurring coumarins from the literature. Additionally, a multi-stage virtual screening combining QSAR modeling, molecular docking, and ADMET prediction was conducted against monoamine oxidase B and acetylcholinesterase, two relevant targets known for their neuroprotective properties and 'disease-modifying' potential in Parkinson's and Alzheimer's disease. Our findings revealed ten coumarin derivatives that may act as dual-target drugs against MAO-B and AChE. Two coumarin candidates were selected from the molecular docking study: CDB0738 and CDB0046 displayed favorable interactions for both proteins as well as suitable ADMET profiles. The stability of the selected coumarins was assessed through 100 ns molecular dynamics simulations which revealed promising stability through key molecular interactions for CDB0738 to act as dual inhibitor of MAO-B and AChE. However, experimental studies are necessary to evaluate the bioactivity of the proposed candidate. The current results may generate an increasing interest in bioprospecting naturally occurring coumarins as potential candidates against relevant macromolecular targets by encouraging virtual screening studies against our chemical library.Communicated by Ramaswamy H. Sarma.
香豆素是药物化学中高度受关注的支架。它存在于许多天然产物中，并被报道具有多种药理学特性。基于香豆素环系统的大量化合物已经被合成，并被发现具有生物活性，如抗惊厥、抗病毒、抗炎、抗菌、抗氧化以及神经保护作用。尽管香豆素具有广泛的活性谱，但天然存在的衍生物尚未得到详细研究。在目前的研究中，创建了一个化学文库，以汇集文献中有关天然香豆素的所有化学信息。此外，还进行了多阶段的虚拟筛选，结合 QSAR 建模、分子对接和 ADMET 预测，针对单胺氧化酶 B 和乙酰胆碱酯酶这两个与神经保护特性相关的靶点，以及帕金森病和阿尔茨海默病的“疾病修饰”潜力。我们的研究结果揭示了十种可能作为 MAO-B 和 AChE 双重作用药物的香豆素衍生物。从分子对接研究中选择了两种香豆素候选物：CDB0738 和 CDB0046 对两种蛋白质均表现出有利的相互作用，并且具有合适的 ADMET 特性。通过 100ns 分子动力学模拟评估了所选香豆素的稳定性，结果表明 CDB0738 通过关键的分子相互作用具有作为 MAO-B 和 AChE 双重抑制剂的良好稳定性。然而，需要进行实验研究来评估所提出候选物的生物活性。目前的结果可能会引起人们对生物勘探天然香豆素作为潜在候选物的兴趣，以鼓励针对我们的化学文库进行虚拟筛选研究，针对相关的大分子靶点。
