Bin Z, Bing Z, Xinchun L
… +3 more, Yang J, Zhanhua L, Lumei D
Future Med Chem
· 2026 Feb · PMID 41493014
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Indole derivatives constitute a structurally heterogeneous and clinically promising class of anticancer agents. Notably, their biological activity stems from targeting multiple hallmarks of cancer, including dysregulated...Indole derivatives constitute a structurally heterogeneous and clinically promising class of anticancer agents. Notably, their biological activity stems from targeting multiple hallmarks of cancer, including dysregulated proliferation, apoptotic evasion, angiogenesis, and epigenetic perturbations, the key processes that drive malignant progression. The indole framework facilitates ready structural modification, enabling specific binding to cancer-selective molecular targets. By comparison, pyrimidine derivatives owe their capacity to act as "molecular mimics" or enzyme inhibitors to their structural analogy to endogenous pyrimidines, which allows them to capitalize on cancer-specific vulnerabilities. Thus, the rational hybridization of indole and pyrimidine scaffolds represents a promising strategy for the development of novel and potent anticancer therapeutics. The present work aims to summarize the current landscape of indole-pyrimidine hybrids with anticancer potential, covering articles published from 2021 to date. The structure-activity relationships and the mechanisms of action are also discussed for further rational design of novel anticancer drug candidates.
Ramsis TM, Hussein S, Abusaif MS
… +8 more, Ragab A, Ammar YA, Ali O, Musa A, Elzaitony AS, Kamal MM, Al-Sanea MM, Fayed EA
Future Med Chem
· 2026 Jan · PMID 41492228
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AIM: Novel hybrids of ibuprofen and naproxen were designed as dual COX-2/5-LOX inhibitors to create safer anti-inflammatory drugs. MATERIALS AND METHODS: The prodrugs were developed through a hybridization molecular appr...AIM: Novel hybrids of ibuprofen and naproxen were designed as dual COX-2/5-LOX inhibitors to create safer anti-inflammatory drugs. MATERIALS AND METHODS: The prodrugs were developed through a hybridization molecular approach; their potency against COX-1, COX-2, and 5-LOX was assessed, alongside measurements of PGE2 levels, NO scavenging, and mTOR and Nrf2 protein expression. Molecular docking was used to predict binding interactions. RESULTS: Hybrids 9 and 10 showed excellent COX-2 inhibition with IC values of 3.3 and 2.0 µM, respectively, and high selectivity indices (SI) of 20.7 and 17.2. Both hybrids also demonstrated substantial 5-LOX inhibition with IC values of 3.1 and 4.2 µM. CONCLUSION: The new hybrids exhibit strong COX-2/5-LOX inhibition, suggesting their structural framework is crucial for developing safer anti-inflammatory drugs.
Future Med Chem
· 2026 Feb · PMID 41489081
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Azetidines are four-membered nitrogen-containing heterocycles that have emerged as vital motifs in drug discovery and medicinal chemistry due to their unique physicochemical and pharmacokinetic profiles. Owing to their d...Azetidines are four-membered nitrogen-containing heterocycles that have emerged as vital motifs in drug discovery and medicinal chemistry due to their unique physicochemical and pharmacokinetic profiles. Owing to their distinctive structural features such as high ring strain, -rich character, and conformational rigidity, which confer enhanced pharmacokinetic properties, solubility, metabolic stability and make them highly attractive scaffolds for the design of bioactive molecules. Natural and synthetic azetidine derivatives demonstrate broad pharmacological potential, ranging from muscarinic antagonists and central nervous system (CNS) modulators to potent antibacterial and anticancer agents. Additionally, significant progress in green and stereoselective synthesis such as visible-light-mediated cycloadditions, strain-release methodologies, and biocatalytic routes have enhanced their accessibility and medicinal relevance. Synthetic derivatives like PF-3635659 (M3 antagonist) and azetidine-modified nicotine analogs highlight the scaffold's utility in neurodegenerative and inflammatory disease therapeutics. Azetidine-based ligands also serve as efficient auxiliaries in asymmetric catalysis and late-stage drug functionalization. Specifically, several Food and Drug Administration (FDA)-approved drugs, such as baricitinib, cobimetinib, sarolaner, and azelnidipine, incorporate azetidine motifs to enhance metabolic stability, receptor selectivity, and pharmacokinetics. Recently, and evaluations have further highlighted their therapeutic promise across oncology, infectious diseases, and inflammation. With their growing impact on drug development and chemical biology, azetidines represent a dynamic frontier for next-generation pharmaceutical innovation and real-world therapeutic success.
Future Med Chem
· 2026 Jan · PMID 41478844
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AIM: To design and synthesize novel dihydropyrimidinone-pyrazole hybrid compounds as potent and selective antitumor agents, exploring their potential mechanism of action. MATERIALS & METHODS: A series of target compounds...AIM: To design and synthesize novel dihydropyrimidinone-pyrazole hybrid compounds as potent and selective antitumor agents, exploring their potential mechanism of action. MATERIALS & METHODS: A series of target compounds were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines: A549 (lung adenocarcinoma), MIA PaCa-2 (pancreatic carcinoma), and HepG2 (hepatoblastoma). Cytotoxicity was also assessed in non-cancerous Vero cells, along with an acute toxicity evaluation in mice. The metabolic stability of the lead compounds was investigated using human liver microsomes. Potential molecular targets were identified through prediction, and the proposed mechanism was further validated via molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays. RESULTS: Compounds and demonstrated potent, broad-spectrum antiproliferative activity in the submicromolar range, exhibiting high selectivity indices against cancer cells and favorable metabolic stability. Integrated computational and enzymatic studies identified Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) as a potential molecular target, suggesting that the antitumor activity may be mediated through its inhibition. CONCLUSION: Compounds and are established as promising anticancer candidates worthy of further development. Future work will focus on comprehensive efficacy studies and deeper mechanistic investigation to advance this novel chemical series.
Future Med Chem
· 2026 Jan · PMID 41457670
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer that remains incurable because it is often detected at an advanced stage, making treatment difficult. MARTIALS AND METHODS: The reaction of free metfo...BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer that remains incurable because it is often detected at an advanced stage, making treatment difficult. MARTIALS AND METHODS: The reaction of free metformin () with isothiocyanate derivatives () and the or with 4-toluenesulfonyl isocyanate () afforded the targeted metformin analogues (). The anticancer impact of these compounds was assessed using cell lines of BJ1, PACA2, and HePG2. RESULTS: Compound had significant cytotoxic effects against PACA2 and HePG2 with mortality 88.30% and 71.20%, respectively. In a chronic study, the body weights of male rats receiving at a dose of 50 mg/kg for 12 consecutive weeks showed an insignificant difference in the percentage change in body weight. Histopathological examination of the pancreas and liver with exhibited normal histological structure of exocrine and endocrine parts. Additionally, normal cardiac myocytes were observed in the heart of rats treated with . CONCLUSIONS: It can be inferred that the daily administration of 50 mg/kg of compound 13 over a duration of 12 weeks did not elicit any substantial alterations in body weight, biochemical, hematological, or histopathological parameters, while concurrently exhibiting pronounced anticancer efficacy against pancreatic ductal adenocarcinoma (PDAC).
Kumar V, Saha P, Jha R
… +2 more, Himani, Narasimhan B
Future Med Chem
· 2026 Feb · PMID 41451830
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Benzimidazole derivatives represent a versatile class of compounds in anticancer drug development due to their unique fused bicyclic structure comprising benzene and imidazole rings. The derivatives are engineered to inc...Benzimidazole derivatives represent a versatile class of compounds in anticancer drug development due to their unique fused bicyclic structure comprising benzene and imidazole rings. The derivatives are engineered to include various chemical modifications, where in most cases, they include other heterocyclic rings or pharmacophores which augment their biological activities and specificity to cancer cells. These anticancer effects are complex and encompass Tubulin polymerization inhibition, DNA intercalation, topoisomerases I and II suppression, apoptotic pathway modulation, and inhibition of major tumor suppressor kinases that include the MAPK and PI3K/AKT. Such activities interfere with the growth of cancer cells, cause cell cycle arrest, induce apoptosis, and prevent angiogenesis and metastasis. Their antitumor and efficacies that include the ability to be used to treat a variety of tumor cell lines in preclinical studies are affirmed by their cytotoxicity and have potential pharmacokinetic and safety profiles. This group of compounds have great clinical potential in the form of targeted therapeutics because of structural flexibility making them useful in precision medicine. Their progression into a clinically useful anticancer drug remains investigating of their structure-activity relationship and molecular docking studies, with benzimidazole derivatives being some of the possible real-life solutions against cancer.
Shukla D, Matore BW, Murmu A
… +3 more, Gawande P, Roy PP, Singh J
Future Med Chem
· 2026 Jan · PMID 41424180
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BACKGROUND: Histone deacetylases (HDAC) are essential epigenetic enzymes that modulate the remodeling of chromatin and transcriptional activity. Overexpression of HDAC has been associated with tumorigenesis, angiogenesis...BACKGROUND: Histone deacetylases (HDAC) are essential epigenetic enzymes that modulate the remodeling of chromatin and transcriptional activity. Overexpression of HDAC has been associated with tumorigenesis, angiogenesis, metastasis, and therapeutic resistance. METHODS: A systematic survey (2008-2025) evaluated the design, mechanism, and structure-activity relationships (SAR) of azole-based hydroxamic acid (ABHA) derivatives as histone deacetylase inhibitors (HDACIs). RESULTS: ABHAs containing 1,3,4-oxadiazole, pyrazole, imidazole, triazole, indazole, thiadiazole, etc. Heterocyclic scaffolds show significant zinc-binding affinity, enhanced pharmacokinetics, and isoform-selective inhibition. Subtle structural variations in heteroaryl substituents, linker architecture, and hydroxamate coordination significantly modulate enzyme selectivity and cytotoxic efficacy. CONCLUSION: ABHA hybrids provide versatile scaffolds with diverse activity for the rational development of next-generation, isoform-selective HDACIs with enhanced potency and therapeutic promise in anticancer drug design.
Future Med Chem
· 2026 Feb · PMID 41416503
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Autophagy-mediated targeted protein degradation, exemplified by technologies such as autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting chimeras (AUTOTACs), and autophagy-targeting chimeras (AUTACs), leverag...Autophagy-mediated targeted protein degradation, exemplified by technologies such as autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting chimeras (AUTOTACs), and autophagy-targeting chimeras (AUTACs), leverages the autophagy-lysosome pathway for the clearance of challenging substrates that often exceed proteasomal capacity. These substrates include large protein aggregates, multi-protein complexes, and even entire organelles. This review synthesizes key advances in the development of autophagy-based degraders since 2022, highlighting their therapeutic potential through exemplar applications. We discuss their utility in oncology, neurodegenerative disorders, and inflammatory/cardiometabolic diseases. These novel modalities have demonstrated potent, selective, and durable substrate elimination , successfully overcoming resistance mechanisms associated with traditional occupancy-driven inhibition. Finally, we summarize the general workflow for developing autophagy-based degraders, outline the current challenges and future directions in this field, and aim to promote fundamental mechanistic studies and innovative medicinal chemistry research, thereby accelerating the clinical translation of autophagy-targeting degraders for the treatment of various human diseases.
Future Med Chem
· 2026 Jan · PMID 41403236
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Cancer therapy is still hampered by key challenges, including drug resistance, poor target selectivity, and narrow therapeutic spectra, driving the pursuit of novel anticancer agents with enhanced efficacy and safety. In...Cancer therapy is still hampered by key challenges, including drug resistance, poor target selectivity, and narrow therapeutic spectra, driving the pursuit of novel anticancer agents with enhanced efficacy and safety. Indole-triazole/pyrazole hybrids, formed by fusing indole scaffolds with triazole/pyrazole, confer inherent structural diversity and high modifiability. Structurally, rational modification of indole/triazole/pyrazole moieties allows optimization of pharmacokinetic properties and improves cancer cell selectivity, minimizing toxicity to normal cells. Functionally, indole-triazole/pyrazole hybrids exhibit multitargeted activity to simultaneously inhibit key oncogenic pathways, addressing the heterogeneity of cancer pathogenesis, while their hybrid structure enhances anticancer potency. This multitargeted mode also aids in overcoming drug resistance, a major bottleneck in clinical therapy. Accordingly, indole-triazole/pyrazole hybrids have emerged as a promising class of anticancer candidates. This review summarizes recent advances in indole-triazole/pyrazole hybrids with anticancer potential, covering articles published from 2021 to the present. To delineate the key molecular features governing anticancer potency, this review further presents a detailed analysis of structure-activity relationships (SARs) and conducts an in-depth exploration of the underlying mechanisms of action.
Deng L, Li L, Li Y
… +3 more, Ma T, Liang S, Tian E
Future Med Chem
· 2026 Jan · PMID 41402050
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Autophagy is an evolutionarily conserved process in eukaryotic cells that degrades and recycles intracellular macromolecules and damaged organelles. It is closely related to a variety of physiological and pathological pr...Autophagy is an evolutionarily conserved process in eukaryotic cells that degrades and recycles intracellular macromolecules and damaged organelles. It is closely related to a variety of physiological and pathological processes. Research on autophagy has become a current hotspot, with protein kinases regarded as crucial components that play essential roles throughout this process. During autophagy, diverse autophagy-related protein kinases continuously regulate different stages. Protein kinases are critical in signal transduction and the regulation of most cellular processes. Therefore, autophagy-associated protein kinases represent potential therapeutic targets for human diseases, and corresponding small-molecule compounds may provide promising therapeutic strategies. This review summarizes the current progress in autophagy research, with a focus on small-molecule drugs that influence autophagy-related kinases and their association with diseases.
Zhuang Y, Cheng Y, Zhu K
… +5 more, Song C, Zhao M, Wang D, Cao X, Liu A
Future Med Chem
· 2026 Jan · PMID 41399951
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Liver cancer, which originates from hepatocytes, ranks among the most commonly diagnosed cancers and stands as a leading cause of cancer-related deaths, primarily due to late diagnosis and its rapid progression. Liver ca...Liver cancer, which originates from hepatocytes, ranks among the most commonly diagnosed cancers and stands as a leading cause of cancer-related deaths, primarily due to late diagnosis and its rapid progression. Liver cancer, especially metastatic liver tumors, often relies on chemotherapy. Still, drug resistance driven by the overexpression of efflux pumps, reduced systemic drug exposure due to hepatic metabolism, low efficacy, and high toxicity creates an urgent need to explore novel chemotherapeutic agents. Hydroxamic acid serves as the zinc-binding group (ZBG) in most histone deacetylase (HDAC) inhibitors and is an important anti-liver cancer pharmacophore. Hydroxamic acid hybrids harness the epigenetic potency of hydroxamic acid through modular pharmacophore integration, providing multitarget efficacy, resistance overcoming, and therapeutic versatility, and thus represent promising candidates for next-generation liver cancer therapies.
Mosić M, Koračak L, Grozdanić M
… +3 more, Jovanović NT, Pešić M, Šegan S
Future Med Chem
· 2026 Jan · PMID 41388987
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AIMS: To evaluate chromatographic lipophilicity of novel artesunate-pyrimidine hybrids and precursors using reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). The impact of measure...AIMS: To evaluate chromatographic lipophilicity of novel artesunate-pyrimidine hybrids and precursors using reversed-phase thin-layer chromatography (RP-TLC) and assess plasma protein binding (PPB). The impact of measured and predicted lipophilicity on pharmacokinetic descriptors was evaluated. Principal component analysis (PCA) explored relationships among lipophilicity, PPB, and physicochemical descriptors. Quantitative structure-activity relationship (QSAR) and partial least squares (PLS) models linked molecular descriptors to cytotoxicity and resistance modulation in nonsmall cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: Lipophilicity was measured by RP-TLC. PPB was determined using human serum albumin (HSA)-modified high-performance liquid chromatography (HPLC). PCA characterized physicochemical-pharmacokinetic correlations. Cytotoxicity in sensitive NCI-H460 and multidrug-resistant (MDR) NCI-H460/R cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. QSAR and PLS models identified key descriptors. RESULTS: Lipophilicity strongly influenced adsorption, distribution, and protein binding. Highly lipophilic hybrids showed near-complete HSA binding. Compound 2k lost cytotoxicity in the presence of albumin, whereas 4k retained potency. Models indicated steric and electronic features, alongside lipophilicity, dictate efficacy and -glycoprotein (-gp) interactions, particularly in resistant cells. CONCLUSIONS: Lipophilicity and steric/electronic descriptors govern distribution, protein binding, and anticancer activity. Integrating these features enables design of hybrids overcoming -gp-mediated multidrug resistance, with hybrid 4k emerging as a promising candidate.
Khalil MS, Al-Karmalawy AA, Abo Elmaaty A
… +2 more, Elsayed GA, Hassan AMA
Future Med Chem
· 2026 Jan · PMID 41388737
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AIM: We aimed to design and synthesize novel pyrimidine-2-thione derivatives (-) as Topoisomerase I/II (Topo I/II) inhibitors with DNA intercalation potential for cancer treatment. MATERIALS & METHODS: Inhibitory concent...AIM: We aimed to design and synthesize novel pyrimidine-2-thione derivatives (-) as Topoisomerase I/II (Topo I/II) inhibitors with DNA intercalation potential for cancer treatment. MATERIALS & METHODS: Inhibitory concentration 50 (IC) against mammary gland breast cancer, hepatocellular carcinoma, and colorectal carcinoma was determined for all compounds. The frontier candidates (, , , , and ) were evaluated for their DNA-binding ability, Topo I, and Topo II inhibiting potential. Moreover, cell cycle and apoptosis analysis were carried out. RESULTS: Compound displayed the best DNA-binding affinity with an IC value of 37.24 µM in comparison to doxorubicin (Dox). Both compounds and showed superior nanomolar Topo I inhibitory potential, compared to Dox. Similarly, compounds and achieved better Topo II inhibition, exceeding that of Dox. It was revealed that compound halted the cell cycle at both the P1 and G2 phases. In addition, compound was able to boost the apoptosis at both the early and late apoptotic phases. CONCLUSION: Consequently, the compounds afforded can be regarded as prominent lead anticancer compounds for further optimization and investigation.
Future Med Chem
· 2026 Jan · PMID 41384335
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Ferroptosis is a form of Regulated Cell Death (RCD) found in recent years. Its typical characteristics are the abnormal accumulation of intracellular iron ions and the accumulation of lipid peroxidation products. Since i...Ferroptosis is a form of Regulated Cell Death (RCD) found in recent years. Its typical characteristics are the abnormal accumulation of intracellular iron ions and the accumulation of lipid peroxidation products. Since its first systematic elucidation in 2012, a large number of studies have shown that ferroptosis is involved in a variety of pathophysiological processes. It has been reported that the pathological process of diabetic cardiovascular diseases (DVD) is closely associated with the activation of ferroptosis. Due to the long-term hyperglycemic environment in diabetic patients, vascular endothelial cells (VECs) are susceptible to ferroptosis, ultimately contributing to vascular dysfunction. Therefore, the development of inhibitors targeting ferroptosis is of great significance for the prevention and treatment of diabetic vascular complications. This review systematically expounds the latest research progress of the molecular mechanism of ferroptosis, and discusses its role in DVD. In addition, this review also comprehensively summarizes the latest advances in the synthesis and application of drugs and specific inhibitors targeting the ferroptosis pathway for disease treatment, thereby providing new therapeutic strategies for DVD.
Zheng J, Zhang Z, Liu J
… +4 more, Shi R, Ren F, Zhavoronkov A, Ding X
Future Med Chem
· 2025 Dec · PMID 41363208
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Cyclin-dependent kinases (CDKs) are central regulators of the cell cycle progression and transcription, making them attractive targets especially in oncology. The clinical success of CDK4/6 inhibitors in hormone receptor...Cyclin-dependent kinases (CDKs) are central regulators of the cell cycle progression and transcription, making them attractive targets especially in oncology. The clinical success of CDK4/6 inhibitors in hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer has highlighted the therapeutic potential of CDK inhibition, along with ongoing clinical evaluation of other CDK-targeted agents. Despite the progress, challenges still remain due to off-target toxicity and the emergence of resistance. Recently, macrocycle-based drug design has gained recognition for its ability to enhance the kinase inhibitory activities and selectivity, improve drug-like properties, and potentially overcome resistance. This review summarizes recent advances (2015-2025) in macrocyclization strategies for CDK inhibitors, tracing the structural modification process from the acyclic scaffolds and highlighting their potential to address key limitations of current therapies.
Farooqui F, Khan AR, Khan MA
… +2 more, Nasibullah M, Ansari JA
Future Med Chem
· 2026 Jan · PMID 41362931
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Cancer remains an incessantly rising cause of mortality worldwide, tempting millions of lives each year and posing a significant global health challenge. Available treatment modalities, including chemotherapy, have been...Cancer remains an incessantly rising cause of mortality worldwide, tempting millions of lives each year and posing a significant global health challenge. Available treatment modalities, including chemotherapy, have been associated with limited scope with severe side effects and complexities, underscoring the imperative need for more efficient and safe curative strategies. In this context, the rational design of multitargeted anticancer agents has gained momentum, aiming to enhance therapeutic outcomes while reducing systemic toxicity. The purine scaffold, a core structural motif found in essential biomolecules, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD), has emerged as a promising pharmacophore in anticancer drug discovery. Notably, several synthetic purine analogues have received clinical approval owing to their potent anticancer activity, particularly when integrated with diverse heterocyclic frameworks. This review comprehensively summarizes the advances made over the past decade in the development of purine-based hybrid molecules, highlighting their mechanistic roles in overcoming drug resistance and targeting multiple oncogenic pathways. The insights presented herein underscore the versatility and therapeutic relevance of purine-based scaffolds and aim to guide future efforts in the rational design and development of drug-resistant and safer anticancer agents.
Milisavljević A, Pražnikar J, Bren U
… +1 more, Jukič M
Future Med Chem
· 2025 Dec · PMID 41328672
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AIMS: Understanding protein-ligand binding site behavior is central to structure-based drug design. We analyzed amino acid composition and interactions in protein-ligand small-molecule binding sites and developed a novel...AIMS: Understanding protein-ligand binding site behavior is central to structure-based drug design. We analyzed amino acid composition and interactions in protein-ligand small-molecule binding sites and developed a novel method for binding site prediction. MATERIALS AND METHODS: We analyzed the PDBBind+ database, which contains the largest protein-ligand binding site dataset known to us, using existing cheminformatics packages and in-house code. We used the resulting data to train a binding site prediction model. RESULTS: Within solvent-accessible binding regions, tryptophan, phenylalanine, tyrosine, methionine, and glycine, were enriched. Interaction analysis revealed hydrophobic contacts as the most frequent, followed by hydrogen bonds, water-bridged hydrogen bonds, salt bridges, π-π, π-cation, and occasional halogen interactions. We introduced the amino acid binding site enrichment index (ABSE), to support small-molecule binding site detection, and developed a model that discriminates binding site sequences from protein surface patches with 0.91 accuracy. CONCLUSIONS: This work offers interpretable composition-interaction relationships and practical tool for binding site characterization. To facilitate application, we provide a free, open-source, fast, bindingsite identification tool (AABS), available at https://gitlab.com/Jukic/aabs. We anticipate that these findings and tool will advance binding site prediction and accelerate computationally intensive drug discovery within medicinal chemistry.
Tok F, Özer FA, Kuzu ZS
… +5 more, Sıcak Y, Kemaloğlu F, Baday S, Sungur FA, Öztürk M
Future Med Chem
· 2026 Jan · PMID 41327764
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AIM: One of the main therapeutic approaches to prevent symptoms and slow the progression of Alzheimer's disease (AD) is cholinesterase inhibitors. For this purpose, some novel 2-pyrazoline-1-carboxamide derivatives based...AIM: One of the main therapeutic approaches to prevent symptoms and slow the progression of Alzheimer's disease (AD) is cholinesterase inhibitors. For this purpose, some novel 2-pyrazoline-1-carboxamide derivatives based on cuminaldehyde were synthesized. MATERIALS AND METHODS: IR, H-NMR, C-NMR and elemental analysis were used to confirm the structures of the synthesized compounds. The antioxidant and cholinesterase (ChE) activities of the compounds were evaluated. Molecular docking and molecular dynamics (MD) simulations were performed to investigate the interaction of the reference and the lead compound at the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) proteins. Molecular Electrostatic Potential (MEP) and Frontier Molecular Orbitals (FMO) for the synthesized compounds were calculated using DFT calculations. RESULTS AND CONCLUSION: Compounds and exhibited the best antioxidant activity. Compounds and were also the most potent compounds against AChE and BChE with IC values of 2.77-3.09 µM and 6.16-6.79 µM, respectively, compared to galantamine (IC = 1.90 µM for AChE and IC = 46.51 µM for BChE). studies showed that compound binds to both targets with higher affinity than the reference compound, galantamine. ADME studies also showed that compound can cross the blood-brain barrier.