Ali Tabasum, Jan Ifat, Ramachandran Rajath, Bashir Rabiah, Andrabi Khurshid Iqbal, Bader Ghulam Nabi
Department of Pharmaceutical Sciences, School of Applied Science and Technology, University of Kashmir, Srinagar, Jammu, Kashmir 190006 India.
GrowthFactorSignalingLaboratory, Department of Biotechnology, University of Kashmir, Kashmir, J&K190006 India.
In Silico Pharmacol. 2024 Sep 28;12(2):89. doi: 10.1007/s40203-024-00259-4. eCollection 2024.
Farnesol is a natural acyclic sesquiterpene alcohol, found in various essential oils such as, lemon grass, citronella, tuberose, neroli, and musk. It has a molecular mass of 222.372 g/mol and chemical formula of C₁₅H₂₆O. The main objective of this study was to assess the effect of farnesol on mTOR and its two downstream effectors, p70S6K and eIF4E, which are implicated in the development of cancer, via molecular dynamic simulation, and docking analysis in an in silico study. A multilayer, primarily computer-based analysis was conducted to assess farnesol's anticancer potential, with a focus on primary cancer targets. From the calculations performed, farnesol showed a binding affinity of - 9.66 kcal/mol, followed by binding affinity of - 7.4 kcal/mol and - 7.8 kcal/mol for mTOR, p70S6K and eIF4E respectively. Rapamycin showed the binding affinity of - 10.45 kcal/mol for mTOR, for p70S6K and eIF4E the calculated binding affinity was - 10.65 kcal/mol and 8.16 kcal/mol respectively. The binding affinity of farnesol was comparable to the standard drug rapamycin indicating its potential as an mTOR inhibitor. Molecular dynamics simulations suggest that the ligands (farnesol and rapamycin) were well trapped within the active site of the protein over a time gap of 50 ns. It is clear that farnesol showed relatively stable MD simulation results, with minor fluctuations and maintains a consistent binding orientation, suggesting a strong and stable interaction with the target proteins when compared to simulation data of standard drug. This study explores the potential of farnesol as an anticancer agent through an in-silico approach, focusing on its interaction with mTOR and its downstream effectors. Inhibition of mTOR signaling pathway may be responsible for the anticancer effect of farnesol. As this pathway plays a crucial role in cell proliferation and survival, making it a significant target in cancer research.
法尼醇是一种天然的无环倍半萜醇，存在于多种香精油中，如柠檬草、香茅、晚香玉、橙花和麝香中。它的分子量为222.372 g/mol，化学式为C₁₅H₂₆O。本研究的主要目的是通过分子动力学模拟和计算机模拟对接分析，评估法尼醇对mTOR及其两个下游效应器p70S6K和eIF4E的影响，这些效应器与癌症的发展有关。进行了一项主要基于计算机的多层分析，以评估法尼醇的抗癌潜力，重点是原发性癌症靶点。从计算结果来看，法尼醇对mTOR、p70S6K和eIF4E的结合亲和力分别为-9.66 kcal/mol、-7.4 kcal/mol和-7.8 kcal/mol。雷帕霉素对mTOR的结合亲和力为-10.45 kcal/mol，对p70S6K和eIF4E的计算结合亲和力分别为-10.65 kcal/mol和8.16 kcal/mol。法尼醇的结合亲和力与标准药物雷帕霉素相当，表明其作为mTOR抑制剂的潜力。分子动力学模拟表明，在50 ns的时间间隔内，配体（法尼醇和雷帕霉素）很好地被困在蛋白质的活性位点内。很明显，法尼醇显示出相对稳定的分子动力学模拟结果，波动较小，并保持一致的结合方向，与标准药物的模拟数据相比，表明与靶蛋白有强烈而稳定的相互作用。本研究通过计算机模拟方法探索了法尼醇作为抗癌剂的潜力，重点是其与mTOR及其下游效应器的相互作用。mTOR信号通路的抑制可能是法尼醇抗癌作用的原因。由于该通路在细胞增殖和存活中起关键作用，使其成为癌症研究中的一个重要靶点。
