Shrestha Ram Lal Swagat, Tamang Ashika, Dhital Sujan, Parajuli Nirmal, Poudel Manila, Adhikari Safal, C Shiva M, Shrestha Aakar, Shrestha Timila, Bharati Samjhana, Maharjan Binita, Marasini Bishnu P, Adhikari Subin Jhashanath
Department of Chemistry, Amrit Campus, Tribhuvan University, Lainchaur, Kathmandu, 44600, Nepal.
Kathmandu Valley College, Syuchatar Bridge, Kalanki, Kathmandu, 44600, Nepal.
Mol Divers. 2025 Apr 28. doi: 10.1007/s11030-025-11191-w.
Neurodegenerative diseases represent a major global health challenge, with cannabinoid receptor type 2 (CB2) emerging as a promising therapeutic target for its role in inflammation modulation and neuroprotection. Sesquiterpene lactone is a class of natural compounds with diverse molecular structures and known biological activities. This study aimed to explore sesquiterpene lactones for their potential as CB2 modulators using computational approaches such as molecular docking, molecular dynamics simulations (MDS), and ADMET predictions, to identify the promising candidates for neurodegenerative disease prophylactics. Out of 85 sesquiterpene lactones evaluated, podachaenin (PubChem CID: 15,828,229) exhibited the highest binding affinity to CB2 (- 12.242 kcal/mol), outperforming that of the native ligand (- 12.168 kcal/mol) and reference drugs apomorphine (- 9.482 kcal/mol), dantrolene (- 8.861 kcal/mol), and galantamine (- 9.689 kcal/mol). Hydrogen bonds as well as alkyl, Pi-alkyl, and van der Waal's interactions were present in the CB2-podachaenin complex providing structural intactness. MDS of 500 ns evaluated the stability of the protein-ligand complex and receptor structure in apo form through geometrical parameters: root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area, and hydrogen bond length. Additionally, the binding free energy change calculation supplemented the initial inferences in terms of thermodynamic stability with a value of - 40.92 ± 4.56 kcal/mol. ADMET profiling also indicated favorable pharmacokinetic and pharmacodynamic properties, similar to that of the reference drugs. The preliminary results identified podachaenin as a possible CB2 modulator for treating neurodegenerative diseases and could be a hit compound in neuro-drug design. Further in vivo and in vitro studies are suggested to validate it as a hit candidate.
神经退行性疾病是一项重大的全球健康挑战，大麻素2型受体（CB2）因其在炎症调节和神经保护中的作用而成为一个有前景的治疗靶点。倍半萜内酯是一类具有多样分子结构和已知生物活性的天然化合物。本研究旨在使用分子对接、分子动力学模拟（MDS）和ADMET预测等计算方法，探索倍半萜内酯作为CB2调节剂的潜力，以确定神经退行性疾病预防的有前景的候选物。在评估的85种倍半萜内酯中，波达查宁（PubChem CID：15828229）对CB2表现出最高的结合亲和力（-12.242千卡/摩尔），优于天然配体（-12.168千卡/摩尔）以及参考药物阿扑吗啡（-9.482千卡/摩尔）、丹曲林（-8.861千卡/摩尔）和加兰他敏（-9.689千卡/摩尔）。CB2-波达查宁复合物中存在氢键以及烷基、π-烷基和范德华相互作用，提供了结构完整性。500纳秒的分子动力学模拟通过几何参数（均方根偏差、均方根波动、回转半径、溶剂可及表面积和氢键长度）评估了蛋白质-配体复合物和无配体形式受体结构的稳定性。此外，结合自由能变化计算以-40.92±4.56千卡/摩尔的值补充了关于热力学稳定性的初步推断。ADMET分析还表明其具有良好的药代动力学和药效学性质，与参考药物相似。初步结果确定波达查宁是一种治疗神经退行性疾病的可能的CB2调节剂，并且可能是神经药物设计中的一个有潜力的化合物。建议进一步进行体内和体外研究以验证其作为有潜力的候选物。
