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- Derleme MakaleYalnız künye2026Scopus SJRQ2Indomethacin as a Multi-target Anticancer Agent via Transmembrane Receptor-mediated Tumor Suppression: The Need for de novo Drug Derivatization
Ozturk, Ebru; Issa, Ghassan; Agar, Soykan
Introduction: Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), has attracted increasing attention for its promising anticancer properties, particularly regarding its crucial effect on transmembrane receptor-mediated signal transduction in different cancers. Besides COX-inhibitory activities, other mechanisms underlying indomethacin's potential as an anticancer agent are being explored, including those related to the mediation of prostaglandin signaling through transmembrane receptors in solid tumors. Methods: In this mini-review, we summarize available information about modulation of transmembrane receptor signaling by indomethacin, including death receptors, EP receptors, receptor tyrosine kinases (RTKs), chemokine receptors, cannabinoid receptors, ACE2, P2X7, IP, and FZD/LRP5/6 receptors associated with Wnt pathways. Results: The presented data indicate that indomethacin may inhibit PGE₂-induced EP signaling, affect EGFR/FGFR and CXCR3 signaling pathways, increase death receptor-mediated apoptosis, and influence various types of receptor cross-talk involved in proliferation, angiogenesis, immune evasion, invasion, and metastasis. However, the most consistent results were obtained in colorectal cancer cells, while the role of indomethacin in breast, ovarian, and prostate cancers appears to be more contextual and receptor-profile dependent. Discussion: Overall, our review suggests that indomethacin functions mainly as a receptor signaling modulator rather than a selective receptor antagonist. The potential clinical application of indomethacin for cancer treatment is hindered by its poor selectivity towards COX enzymes, toxicity, and lack of specificity. Conclusion: Despite the possibility of using indomethacin as a template structure for creating more selective drugs, it seems that indomethacin cannot serve as a drug for anticancer therapy alone. This conclusion specifically positions parent indomethacin as a chemically modifiable scaffold for rational derivative development rather than as a final therapeutic endpoint. 2026, Bentham Science Publishers
- MakaleYalnız künye2025Scopus SJRQ3De novo Drug Design and Repurposing to Suppress Liver Cancer via VEGF-R1 Mechanism: Comprehensive Molecular Docking, Molecular Dynamics Simulations and ADME Estimation
Agar, Soykan
Aim: The aim is to halt the progression of liver cancer (Hepatocellular carcinoma) by suppressing the VEGF-R1 receptor using Myricetin and its de novo-designed analogues. Background: 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. Objective: Creating a pharmaceutical chemistry table regarding “Structure-Activity Relationship of New Compounds on anticancer”. To do so, Myricetin and its de novo 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. Methods: 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. Results: 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 Fluorine-derivatized 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. Conclusion: This study highlighted the significant potential of Myricetin as an anti-cancer drug when modified with specific functional groups. Through comprehensive in silico 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 in vitro and in vivo investigations of these molecules as potential drugs in cancer research.
AtıfScopus3WoS5OpenAlex8
İncele - MakaleAçık Erişim2024Scopus SJRQ3Evaluation of Main Lacrimal Gland through Shear-Wave Ultrasound Elastography in Patients with Low Schirmer Value
Yılmaz, Hakan; Güneş, İrfan Botan
Objective: To compare main lacrimal gland values through shear-wave elastography (SWE) in patients with low Schirmer value and unspecified Sjögren's syndrome (SS) with healthy controls. Material and method: Admitted to the ophthalmology department with Schirmer value <10 mm, randomly selected 46 eyes of 46 patients evaluated for Sjögren's syndrome (SS) in the rheumatology department between December 2022 and April 2023 were classified as low Schirmer group (LSG). Randomly selected 48 eyes of 48 patients at a similar age with Schirmer value >10 mm were included as controls. Main lacrimal gland SWE measurements in LSG and control groups were recorded and compared as meter/second (m/sec). Results: Mean SWE values of the main lacrimal gland were measured as 2.78±0.66 m/sec and 2.26±0.29 m/sec in LSG and controls. SWE measurements were significantly higher in LSG patients than in controls (p<0.001). No significant correlation was found in the analysis between the Schirmer and the main lacrimal gland SWE values in LSG patients (p=0.702, r=0.058). No significant correlation was also detected between the Schirmer and main lacrimal gland SWE values in controls (p=0.097, r=0.242). No significant relationship was also found between age, gender, body mass index (BMI), and SWE values (p=0.351, p=0.493, p=0.328, respectively). Conclusion: Mean SWE value of the main lacrimal gland was determined as significantly higher in patients with aqueous lacrimal insufficiency without SS than in controls. We consider that SWE measurements may be an imaging method to support the diagnosis of aqueous lacrimal insufficiency and used in follow-ups of those with dry eye syndrome (DES) in the future.
AtıfScopus7WoS6OpenAlex5İncele - DergiCurrent Drug Targets
- DergiCurrent Medical Imaging
- DergiMedicinal Chemistry