Agar Soykan
AGAR In Silico Drug Design Center, Department of Biochemistry, Faculty of Pharmacy, Kocaeli Health and Technology University, Yeniköy Mahallesi Ilıca Caddesi No: 29, 41090, Başiskele/Kocaeli, Türkiye.
Med Chem. 2025;21(6):501-515. doi: 10.2174/0115734064333811240928105309.
The aim is to halt the progression of liver cancer (Hepatocellular carcinoma) by suppressing the VEGF-R1 receptor using Myricetin and its -designed analogues.
VEGF/VEGFR autocrine signalling promotes the growth, progression, and metastasis of Hepatocellular carcinoma, making the development of molecularly targeted therapies highly feasible. Invasive and metastatic behaviours in various cancers, including hepatocellular carcinoma (HCC), are closely monitored through the use of VEGF signalling pathway inhibitors. Specifically in HCC, VEGFR-1 facilitates the invasive capabilities of cancer cells primarily by triggering the epithelial-mesenchymal transition (EMT) process. VEGFR-1 significantly influences the activity of proteolytic enzymes that are critical for the invasive behaviour of HCC cells. Notably, a novel mechanism has been discovered where VEGFR-1 activation leads to the upregulation of MMP-9, thereby enhancing the invasiveness of HCC cells. The scientists, in their study, have elaborated on the various antiangiogenic agents developed for the treatment of HCC. They have highlighted clinical trials that explore the efficacy of these treatments, which include the application of monoclonal antibodies and small-molecule kinase inhibitors designed to target specific pathways involved in tumour angiogenesis and growth.
Creating a pharmaceutical chemistry table regarding "Structure-Activity Relationship of New Compounds on anticancer''. To do so, Myricetin and its designed structured variants were used in molecular docking, molecular dynamics, cluster analyses, and 1H NMR estimation to specifically understand and enhance the mechanism of suppressing the VEGF-R1 receptor.
Proper ligands (Myricetin and its analogues) and receptor (VEGF-R1) preparations, and optimizations were done using the density functional theory (DFT)/B3LYP function along with the 6-31G(d,p) basis set principle in the latest software programs such as Gaussian 09, Gauss View 6.0 and Avogadro. Then using PyRx and Autodock Vina 1.1.2., many molecular docking trials were achieved with 100 posed simulations in each run. An extensive cluster analysis was performed to identify the most optimal docking poses with the highest accumulation and most favourable binding interactions, ensuring the accuracy of the study. The docking configurations that exhibited the most precise and accurate poses with lowest inhibition constants were chosen as initial structured data for subsequent Molecular Dynamics (MD) simulations for each drug candidate. To verify the molecular docking results, MD runs were achieved in our supercomputers and the trajectory analyses were made. The data confirmed what was found in molecular docking results, verifying the high efficiency of the druggable molecules' inhibition towards VEGF-R1.
Amine-derivatized Myricetin has a significantly high docking score (-10.56 kcal/mol) and great inhibition constant compared to pristine Myricetin (-4.77 kcal/mol) itself while Fluorinederivatized Myricetin (-6.45 kcal/mol) has an affinity towards VEGF-R1 between the first two molecules. Thus, the structure-activity relationship concerning pharmaceutical chemistry aspects of all the molecules studied, yielded us a great insight into what Myricetin's organic structure possesses towards inhibiting the progression of Liver Cancer. Also, ADME studies showed that both Amine and Fluorined-derivatized Myricetin molecules are good drug candidates.
This study highlighted the significant potential of Myricetin as an anti-cancer drug when modified with specific functional groups. Through comprehensive computational analyses, our research group enhanced Myricetin's inhibitory capabilities by derivatizing its Hydroxyl group with Amine and Fluorine, resulting in improved docking scores and inhibition constants. The findings from molecular docking and MD simulations provide a promising foundation for future and investigations of these molecules as potential drugs in cancer research.
旨在通过使用杨梅素及其设计的类似物抑制血管内皮生长因子受体1（VEGF-R1），来阻止肝癌（肝细胞癌）的进展。
VEGF/VEGFR自分泌信号传导促进肝细胞癌的生长、进展和转移，这使得分子靶向治疗的开发具有高度可行性。通过使用VEGF信号通路抑制剂，可以密切监测包括肝细胞癌（HCC）在内的各种癌症的侵袭和转移行为。具体到HCC，VEGFR-1主要通过触发上皮-间质转化（EMT）过程来促进癌细胞的侵袭能力。VEGFR-1显著影响对HCC细胞侵袭行为至关重要的蛋白水解酶的活性。值得注意的是，已经发现了一种新机制，即VEGFR-1激活导致基质金属蛋白酶-9（MMP-9）上调，从而增强HCC细胞的侵袭性。科学家们在他们的研究中阐述了为治疗HCC而开发的各种抗血管生成药物。他们强调了探索这些治疗方法疗效的临床试验，其中包括应用单克隆抗体和小分子激酶抑制剂，这些药物旨在靶向参与肿瘤血管生成和生长的特定途径。
创建一个关于“新化合物抗癌的构效关系”的药物化学表。为此，杨梅素及其设计的结构变体被用于分子对接、分子动力学、聚类分析和1H NMR估计，以具体了解和增强抑制VEGF-R1受体的机制。
使用密度泛函理论（DFT）/B3LYP函数以及6-31G(d,p)基组原理，在诸如Gaussian 09、Gauss View 6.0和Avogadro等最新软件程序中对合适的配体（杨梅素及其类似物）和受体（VEGF-R1）进行制备和优化。然后使用PyRx和Autodock Vina 1.1.2.，每次运行进行100次构象模拟，完成多次分子对接试验。进行了广泛的聚类分析，以确定具有最高聚集度和最有利结合相互作用的最佳对接构象，确保研究的准确性。选择表现出最精确和准确构象且抑制常数最低的对接构型作为每种候选药物后续分子动力学（MD）模拟的初始结构数据。为了验证分子对接结果，在我们的超级计算机上进行了MD运行并进行了轨迹分析。数据证实了分子对接结果中的发现，验证了可药物化分子对VEGF-R1抑制的高效性。
与原始杨梅素本身（-4.77 kcal/mol）相比，胺衍生化的杨梅素具有显著更高的对接分数（-10.56 kcal/mol）和更大的抑制常数，而氟衍生化的杨梅素（-6.45 kcal/mol）对VEGF-R1的亲和力介于前两个分子之间。因此，所研究的所有分子在药物化学方面的构效关系，让我们深入了解了杨梅素的有机结构对抑制肝癌进展所具有的作用。此外，药物代谢动力学研究表明，胺衍生化和氟衍生化的杨梅素分子都是良好的候选药物。
本研究突出了杨梅素经特定官能团修饰后作为抗癌药物的巨大潜力。通过全面的计算分析，我们的研究小组通过用胺和氟对杨梅素的羟基进行衍生化，增强了其抑制能力，从而提高了对接分数和抑制常数。分子对接和MD模拟的结果为这些分子作为癌症研究中的潜在药物的未来研究提供了有希望的基础。
