Current Medicinal Chemistry - Volume 33, Issue 7, 2026

Colorectal cancer (CRC) stands as the third most widespread cancer worldwide in both men and women, witnessing a concerning rise, especially in younger demographics. Abnormal activation of the Non-Receptor Tyrosine Kinase c-Src has been linked to the advancement of several human cancers, including colorectal, breast, lung, and pancreatic ones. The interaction between c-Src and Hexokinase 2 (HK2) triggers enzyme phosphorylation, significantly boosting glycolysis, and ultimately contributing to the development of CRC.

The objectives of this study are to examine the influence of newly identified mutations on the interaction between c-Src and the HK2 enzyme and to discover potent phytocompounds capable of disrupting this interaction.

In this study, we utilized molecular docking to check the effect of the identified mutation on the binding of c-Src with HK2. Virtual drug screening, MD simulation, and binding free energy were employed to identify potent drugs against the binding interface of c-Src and HK2.

Among these mutations, six (W151C, L272P, A296S, A330D, R391H, and P434A) were observed to significantly disrupt the stability of the c-Src structure. Additionally, through molecular docking analysis, we demonstrated that the mutant forms of c-Src exhibited high binding affinities with HK2. The wildtype showed a docking score of -271.80 kcal/mol, while the mutants displayed scores of -280.77 kcal/mol, -369.01 kcal/mol, -324.41 kcal/mol, -362.18 kcal/mol, 266.77 kcal/mol, and -243.28 kcal/mol for W151C, L272P, A296S, A330D, R391H, and P434A respectively. Furthermore, we identified five lead phytocompounds showing strong potential to impede the binding of c-Src with HK2 enzyme, essential for colon cancer progression. These compounds exhibit robust bonding with c-Src with docking scores of -7.37 kcal/mol, -7.26 kcal/mol, -6.88 kcal/mol, -6.81 kcal/mol, and -6.73 kcal/mol. Moreover, these compounds demonstrate dynamic stability, structural compactness, and the lowest residual fluctuation during MD simulation. The binding free energies for the top five hits (-42.44±0.28 kcal/mol, -28.31±0.25 kcal/mol, -34.95±0.44 kcal/mol, -38.92±0.25 kcal/mol, and -30.34±0.27 kcal/mol), further affirm the strong interaction of these drugs with c-Src which might impede the cascade of events that drive the progression of colon cancer.

Our findings serve as a promising foundation, paving the way for future discoveries in the fight against colorectal cancer.

Hepatitis B Virus-Related Hepatocellular Carcinoma (HBV-HCC) constitutes a formidable global health challenge, demanding an in-depth understanding of its intricate pathogenesis. The research conducted a comprehensive analysis of the multifaceted relationship between HBV-HCC. It further examined the potential of Taraxacum officinale, which could serve as an effective adjunct therapy in treating HBV-associated HCC. Our approach integrates network pharmacology, pathway analysis, molecular docking, and dynamics simulations, offering an intricate unraveling of the molecular mechanisms that underlie T. officinale's potential impact on HBV-HCC.

Additionally, we delve into microarray analysis to unearth differentially expressed genes (DEGs) associated with HBV-HCC, molecular docking to validate compound interactions with key proteins, and molecular dynamics simulations to elucidate the stability of these interactions. These multifaceted approaches enhance our understanding of T. officinale's therapeutic potential.

This work represents a significant advancement toward the development of more effective strategies for the management of this challenging disease, offering a comprehensive exploration of T. officinale's therapeutic prowess. Within this multidimensional framework, we identify CDK1, SERPINE1, and PTGS2 as promising therapeutic targets, shedding light on the molecular intricacies of disease progression. Further, Homoorientin from T. officinale's demonstrates a strong binding affinity with proteins CDK1, SERPINE1, and PTGS2, suggesting a potential synergistic effect in therapeutic applications. Moreover, our enrichment analysis uncovers a rich tapestry of pathways enriched in HBV-HCC, providing insights into the multifaceted landscape of disease complexity.

These findings not only pave the way for potential targeted therapies but also deepen our comprehension of the intricate molecular underpinnings of HBV-HCC.This work represents a significant advancement toward the development of more effective strategies for the management of this challenging disease, offering a multifaceted exploration of T. officinale's therapeutic potential.

Endometrial carcinoma (EC) is a type of cancer that originates in the lining of the uterus, known as the endometrium. It is associated with various treatment options such as surgery, radiation therapy, chemotherapy, and hormone therapy, each presenting unique challenges and limitations. Beta-catenin, a protein involved in the development and progression of several cancers, including EC, plays a crucial role. Abnormal beta-catenin signaling is often linked to the emergence of specific EC subtypes, affecting tumor growth and invasion.

The study's objective is to identify compounds targeting the beta-catenin protein for treating endometrial cancer (EC) using in silico drug design. Our approach includes molecular docking to evaluate binding affinities, ADME profiling for pharmacokinetic properties, toxicity assessments, and molecular dynamics simulations to assess compound stability and interactions.

Approximately one thousand anti-cancer phytochemicals were sourced from PubChem and subjected to molecular docking simulations against the beta-catenin protein. The compounds were evaluated based on their binding affinities, with the top five selected for further analysis. These five molecules underwent toxicity and ADME profiling. The Prediction of Activity Spectra for Substances (PASS) tool was used to identify compounds targeting CTNNB1. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to establish quantitative structure-activity relationship (QSAR) models for the five CTNNB1 antagonist molecules.

The selected five compounds, namely Pazopanib, Binimetinib, Telatinib, 4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-((5-nitrothiazol-2-yl)thio)-1H-1,2,4-triazol-5(4H)-one, and Ribavirin, demonstrated efficacy against CTNN1. MD simulations of the docked complexes confirmed the stability of these drugs in binding to the target protein. All five molecules showed promising safety and effectiveness profiles according to their ADME and toxicity evaluations.

Through a comprehensive screening process employing in silico drug design methods, this study successfully identified five potential human anticancer drug candidates targeting the beta-catenin protein. These findings offer a foundation for further experimental validation and development towards the treatment of EC.

Aerobic glycolysis is crucial for cancer cells to survive, grow, and progress. In the current study, the anti-cancer effects of astragalin (ASG) on breast cancer cells and in the glycolytic pathway through AMPK/mTOR have been evaluated.

The objective of this study was to examine the impact of ASG, a natural flavonoid, on glycolysis via targeting AMPK/mTOR signalling in MDA-MB-231 breast cancer cells.

The study utilized ASG, which was isolated from Haplophyllum tuberculatum. The cells were treated with different concentrations of ASG (20 and 40 µg/mL), and anti-glycolytic activities were measured through cell proliferation, expression of glycolytic enzymes (HK-2, LDH-A, GLUT-1), glucose uptake, and lactate concentration assays. The MTT assay was used to assess cellular proliferation, while the glucose uptake and lactate levels were determined by employing colorimetric assays. The mRNA expression of target glycolytic enzymes was determined by qRT-PCR. The protein levels of glycolytic targets, as well as that of AMPK and mTOR, were determined by western blot. in silico docking of ASG was done with mTOR and AMPK proteins.

Astragalin exhibited dose- and time-dependent anti-proliferative effects in MDA-MB-231 cells. In breast cancer cells, the mRNA and protein expression of GLUT-1, LDH-A, and HK-2 were all significantly downregulated after receiving ASG treatments. Furthermore, after ASG treatments, MDA-MB231 cells showed a significant decrease in lactate and glucose uptake compared to control cells. Mechanistically, ASG increased AMPK activation and suppressed mTOR activation in these cells. The inhibitory role of ASG on aerobic glycolysis was prevented by treatments with compound C (an AMPK inhibitor). However, combined treatment of compound C and ASG could nullify the ASG-induced anti-glycolysis effect and restore the level of p-AMPK and p-mTOR in MDA-MB231 cells. The results from molecular docking predicted that ASG had the potential to bind AMPK and mTOR, with free energy for binding, -8.2 kcal/mol and -8.1 kcal/mol, respectively.

Taken together, the findings from this study indicated that ASG might modulate the AMPK/mTOR pathway to inhibit aerobic glycolysis and proliferation of MDA-MB231 breast cancer.

Prolyl oligopeptidase (POP) is a pivotal druggable target implicated in diverse biological processes and linked to the development of various ailments, including neurodegenerative disorders. While conventional peptide-based inhibitors have been a centerpiece, their limitations, such as restricted bioavailability, necessitate exploration of non-peptidic inhibitors for their therapeutic potential.

This study focuses on designing, synthesizing, and assessing morpholine-based hydrazones targeting the catalytic serine residue of POP. The hydrazones (5a-o), reported as moderately potent analogs compared to the renowned Z-Pro-Prolinal, demonstrated in vitro POP inhibition with IC50 values ranging from 13.60 ± 2.51 to 36.51 ± 1.82 μM. The derivative 5h, with an IC50 of 13.60 ± 2.51 μM, emerged as the most potent inhibitor.

Moreover, the in vitro kinetic study of compound 5h indicated that it exhibited concentration-dependent type of inhibition. In silico docking studies of 5h revealed robust interactions in the POP enzyme's active site, yielding a docking score of ˗6.30 Kcal/mol, consistent with experimental results.

All findings underscored the potential of synthesized derivatives for drug development.

Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia.

The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde-based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 µM).

Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 µM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 µM) indicated competitive inhibition of the aforementioned enzyme.

Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

Silent information regulator two homologue one (SIRT1) is an emerging target for managing metabolic disorders. This study aimed to synthesize novel 5-(substituted phenyl)-2-aryl benzimidazole derivatives and evaluate them for SIRT1 activation.

The compounds were designed according to the findings of the QSAR models framed in our previous studies. Molecular docking and dynamics studies were also performed to explore the interactions of designed compounds with the active site of the SIRT1 enzyme using AutoDock Vina and Schrödinger Maestro version 11.8.012, respectively. Compounds with good binding affinity were synthesized by Suzuki-Miyaura cross-coupling and spectrally characterized. The molecules were evaluated for their in vitro SIRT1 activation properties using a fluorescent screening kit. Based on the results of in vitro assay, a structure-activity relationship was established. SwissADME was employed to calculate the pharmacokinetics characteristics of the synthesized molecules.

The molecular docking studies revealed that all the activators were effectively docked in the catalytic active site. All compounds demonstrated interactions with important amino acids like Glu230 and Arg446. In molecular dynamics simulations, the root mean square deviation (RMSD) of compound 5m and protein SIRT1 remained stable, i.e., below 3mm. Compound 5m, 4-(2-(3,4-dihydroxy-5-nitrophenyl)-1H-benzo[d]imidazol-5-yl)benzaldehyde, was the most potent compound with an EC50 value of 0.006 mM (±0.001) and maximum activation of 240.5%. All the synthesized compounds had acceptable theoretical ADME profiles, and drug-likeness properties complied with Lipinski’s rule.

According to the findings, synthesized compounds may be viable leads for SIRT1 activators and may be used to advance preclinical in vivo research utilizing animal models.

The high incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) as a hepatic component of metabolic syndrome is attributed to the ongoing rise in obesity rates. Given the beneficial effects of hydroxychloroquine (HCQ) on metabolism, there is growing interest in combining it with fisetin (FSN), a natural product, to treat NAFLD more effectively.

The efficacy and safety of the combined therapy of FSN and HCQ in animal models of NAFLD were assessed, focusing on liver function, insulin sensitivity, oxidative stress, and inflammation.

C57BL/6J mice were fed either a standard chow diet or a high-fat diet to induce NAFLD. FSN and HCQ were administered to the mice, and biochemical parameters related to glucose and lipid metabolism, as well as oxidative stress markers, were measured in serum and liver tissue. Analyses included Oil Red O staining, mRNA levels of key lipid metabolism molecules, and immunohistochemical assessments of macrophage infiltration. Statistical analyses were performed using GraphPad Prism 9.

While the HCQ group exhibited some improvements in certain markers, it also displayed adverse effects. The FSN group, particularly the FSN + HCQ group, effectively reversed insulin sensitivity, glucose homeostasis, and NAFLD markers by modulating lipid metabolism and inflammation pathways. HCQ exacerbated oxidative stress, which was mitigated by the effects of FSN.

Despite concerns regarding the long-term side effects of HCQ, its combination with FSN presents a promising approach for improving the management of NAFLD by reducing risks and enhancing outcomes.