Pharmacophoric Features Research Articles

Discovery of novel A2AR antagonist via 3D-QSAR pharmacophore modeling: neuroprotective effects in 6-OHDA-induced SH-SY5Y cells and haloperidol-induced Parkinsonism in C57 bl/6 mice.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder which is caused by abrupt degeneration of dopaminergic neuronal cells in the substantia nigra pars compacta (SNPc) area of the midbrain. Adenosine A2A receptors have become promising therapeutic targets for PD; however, many A2A receptor antagonists face challenges, such as limited accessibility or failure in clinical trials due to poor selectivity and bioavailability. To identify novel A2A receptor antagonists, a 3D-QSAR-pharmacophore modeling approach was employed, involving virtual screening of ZINC, NCI, and MayBridge databases. The virtual hits were filtered via ADMET criteria to select compounds with favorable bioavailability and solubility profiles. From the MayBridge database, a potent monocyclic A2A receptor antagonist, AW00032 (N-(furan-2-ylmethyl)-5-methylthiazole-4-yl) thiophene-2-sulfonamide, was identified. AW00032 possessed key pharmacophoric features: two lipophilic hydrogen bond acceptors, one hydrophobic aliphatic/aromatic group, and one aromatic ring. Docking analysis revealed AW00032 had a strong binding affinity for A2A receptors (1.23nM, ∆G -10.49kcal/mol), and its ADMET profile indicated good bioavailability. In 6-OHDA induced SH-SY5Y cells, AW00032 increased dopamine levels and tyrosine hydroxylase (TH) expression, demonstrating its potential as an A2A receptor antagonist. AW00032, discovered through 3D-QSAR pharmacophore modeling, also reduced reactive oxygen species (ROS) levels and showed depletion in mitochondrial dysfunction in 6-OHDA-induced SH-SY5Y cells. It exhibited A2A receptor antagonist activity comparable to the standard antagonist ZM241385, partially restoring dopamine and TH levels. Furthermore, AW00032 improved behavioral symptoms in haloperidol-induced C-57 bl/6 mice.

Catalytic Lysine745 targeting strategy in fourth-generation EGFR tyrosine kinase inhibitors to address C797S mutation resistance.

Overcoming resistance to third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib, particularly due to the emergence of the C797S mutation, remains a key challenge in non-small cell lung cancer (NSCLC) therapy. This review highlights recent advancements in the development of fourth-generation EGFR inhibitors that specifically target the catalytic Lys745 residue, aiming to overcome resistance associated with Osimertinib. Both covalent and non-covalent inhibitors targeting Lys745 were explored, using warheads like sulfonyl fluoride, phosphine oxides, esters, and trisubstituted imidazoles. Sulfonyl fluoride was particularly effective in forming covalent bonds with Lys745, while non-covalent analogues demonstrated flexibility with reduced off-target effects. The manuscript highlights the importance of warhead design, molecular docking, protein XRD study and structure-activity relationships (SAR) for optimizing Lys745-targeting inhibitors. The study suggests that hybrid scaffolds combining key pharmacophoric features from Osimertinib and Brigatinib along with Lys745 targeting warheads, could enhance selectivity and potency. Future efforts should focus on refining bioavailability, identifying new scaffolds by employing drug design strategies. Fourth-generation TKIs targeting Lys745 offer a novel therapeutic avenue, potentially overcoming mutation-induced resistance and improving NSCLC treatment outcomes. This approach represents a critical advancement toward durable clinical responses in patients with drug-resistant cancer.

Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors

This paper describes the design, development, synthesis, in silico, and in vitro evaluation of fourteen novel heterocycle hybrids as inhibitors of the α-glucosidase enzyme. The primary aim of this study was to explore the potential of novel pyrazole-phthalazine hybrids as selective inhibitors of α-glucosidase, an enzyme involved in carbohydrate metabolism, which plays a key role in the management of type 2 diabetes. The rationale for this study stems from the need for new, more effective inhibitors of α-glucosidase with improved efficacy and safety profiles compared to currently available therapies like Acarbose. The synthesized compounds were tested against the yeast α-glucosidase enzyme and showed significantly higher activity than the standard drug Acarbose. The IC50 values ranged from 13.66 ± 0.009 to 494 ± 0.006 μM, compared to the standard drug Acarbose (IC50 = 720.18 ± 0.008). The most effective α-glucosidase inhibitor, 2-acetyl-1-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3-methyl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione (8l), was identified through a kinetic binding study that yielded an inhibition constant, Ki, of 34.75 µM. All of the pharmacophoric features used in the hybrid design were found to be involved in the interaction with the enzyme’s active site, as expected. Moreover, molecular dynamic simulation and the absorption, distribution, metabolism, and excretion (ADME) have been performed.

Integrating Machine Learning and Pharmacophore Features for Enhanced Prediction of H1 Receptor Blockers.

Histamine Type I Receptor Antagonists (H1 blockers) are widely used to mitigate histamine-induced inflammation, particularly in allergic reactions. Histamine, a biogenic amine found in endothelial cells, vascular smooth muscle, bronchial smooth muscle, and the hypothalamus, is a key player in these responses. H1 blockers are essential in cough syrups and flu medications and are divided into two generations: first-generation H1 blockers, which are sedating and have numerous side effects, and second-generation blockers, which are non-sedating and generally less toxic but may still exhibit cross-reactivity with other receptors. In this study, a comprehensive database of compounds was utilized alongside fexofenadine as a benchmark to discover compounds with potentially superior efficacy and reduced side effect profiles. In particular, multidimensional K-means clustering, a machine-learning technique, was applied to identify compounds with chemical structures similar to fexofenadine. Utilizing computational prediction of pharmacokinetic profile and molecular docking experiments, the action of these drugs on the H1 receptor was assessed. Furthermore, the crossreactivity of antihistamines was investigated by conducting a structure-based pharmacophore feature analysis of the docked poses of highly toxic antihistamines with various receptors. By identifying and proposing the removal of common toxic features, we aim to facilitate the development of antihistamines with fewer adverse effects.

Identification of HIV-1 Reverse Transcriptase-Associated Ribonuclease H Inhibitors Based on 2-Hydroxy-1,4-naphthoquinone Mannich Bases

There is a strong demand for new and efficient antiviral compounds. A series of 2-hydroxy-1,4-naphthoquinone Mannich bases were screened for their HIV-1-RNase H inhibitory activity. An HIV-1-RNase H assay was used to study the RNase H inhibition by the test compounds. Docking of active derivatives into the active site of the enzyme was carried out. Compounds 1e and 2k showed distinctly higher HIV-1-RNase H inhibitory activity (IC50 = 2.8–3.1 µM) than the known inhibitors RDS1759 and compound 13. The binding mode and possible interactions of 1e and 2k with the HIV-1-RNase H active site were determined using molecular docking, which led to the identification of salient and concealed pharmacophoric features of these molecules. The docking analysis revealed that there are significant differences in the binding mode of these compounds within the active site of the target enzyme. A selection of HIV-1-RNase H-inhibitory Mannich bases was tested for antiviral activity against HIV-1, and compound 2k showed the highest activity at low toxicity to host cells. The lawsone Mannich bases 1e and 2k also underwent a preliminary screening for activity against SARS-CoV-2, and compound 1e was found to inhibit SARS-CoV-2 replication (IC50 = 11.2 µM).

Recent Advances in the Development of Greener Methodologies for the Synthesis of Benzothiazoles.

The benzothiazole ring system has been recognised with crucial pharmacophoric features being present among various approved drugs and clinical and pre-clinical candidates. The medicinal importance of this privileged scaffold stimulated the interest of synthetic medicinal/ organic chemists for the synthesis of its derivatives due to their diverse biological applications. In most of the reports in the literature, benzothiazoles were synthesized by cyclocondensation of 2- aminothiophenol with either carboxylic acid and its derivatives or aldehydes. However, many of these procedures involve reaction conditions that are not in conformity with sustainable chemistry development. The negative impact of chemicals and their manufacturing processes on the environment, human health, and biodiversity raises safety concerns. On the other hand, the utilization of non-renewable energy sources, use of rare earth metals as catalysts, involvement of costly chemicals, prolonged reaction time at high temperatures, and considerable waste generation diminish the greener impact of these reaction methodologies and make them non-sustainable. In order to avoid such drawbacks of the non-sustainable practices in the synthesis of benzothiazoles, there have been continuous efforts to develop greener methodologies for the construction of this bioactive scaffold. This review aims to delve into the literature reports on the recent advancements in the development of greener methodologies for the synthesis of bioactive benzothiazoles.

Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer's disease.

Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.

Design and Synthesis of Topoisomerases-Histone Deacetylase Dual Targeted Quinoline-Bridged Hydroxamates as Anticancer Agents.

The multifactorial nature of cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their anticancer potential. Our findings revealed that the compound 5c significantly produced anticancer effects in vitro and in vivo by reducing the tumor growth and its size in the A549 cell-induced lung cancer xenograft model through multiple mechanisms, primarily by multi-inhibition of hTopoI/II and HDACs, especially HDAC1 via atypical binding. The present paper discusses detailed mechanistic biological investigations, structure-activity effects supported by computational docking studies, and DMPK studies and provides future scope for lead optimization and modification.

The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach.

The Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 (G protein-coupled bile acid receptor), is a membrane-type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore-based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit-3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.

Novel rhodanine-thiazole hybrids as potential antidiabetic agents: a structure-based drug design approach.

New rhodanine-thiazole clubbed compounds (7a-7l) were synthesised and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro HPA, HLAG inhibition, and peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression assays. Through the biological study, compound 7f showed promising inhibitory activity against HPA with an IC50 value of 27.13 ± 1.02 μM and 7l exhibited better inhibition against HLAG with an IC50 value of 24.21 ± 1.12 μM. In addition, Lineweaver-Burk plot analysis suggested that 7l and 7f behaved as a mixed type of HLAG and HPA inhibitor and further, compound 7f showed significant PPAR-γ expression as compared to controls in a dose dependent manner; the expression can be attributed to its mapped pharmacophoric features with a phase screen score of 1.28 and vector score of 0.62. The proteins modulated by compounds include AMY2A, PPAR, and GAA proteins via MAPK, PPAR signalling pathways identified by cluster analysis and justified by molecular docking studies and MD trajectory analysis to evaluate the binding orientation and stability of the molecules, and the energy profiles of the molecules, both in complex with the protein, were assessed using MM/GBSA and DFT calculations, respectively. Finally, the pharmacokinetic profile was determined using ADMET analysis. Thus, from the above findings, it may demonstrate that rhodanine-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.

Energetics of substrate transport in proton-dependent oligopeptide transporters

The PepTSo transporter mediates the transport of peptides across biological membranes. Despite advancements in structural biology, including cryogenic electron microscopy structures resolving PepTSo in different states, the molecular basis of peptide recognition and transport by PepTSo is not fully elucidated. In this study, we used molecular dynamics simulations, Markov State Models (MSMs), and Transition Path Theory (TPT) to investigate the transport mechanism of an alanine-alanine peptide (Ala-Ala) through the PepTSo transporter. Our simulations revealed conformational changes and key intermediate states involved in peptide translocation. We observed that the presence of the Ala-Ala peptide substrate lowers the free energy barriers associated with transition to the inward-facing state. We also show a proton transport model and analyzed the pharmacophore features of intermediate states, providing insights for rational drug design. These findings highlight the significance of substrate binding in modulating the conformational dynamics of PepTSo and identify critical residues that facilitate transport.

An overview ofmatrix metalloproteinase-12 in multiple disease conditions, potential selective inhibitors, and drug designing strategies.

Matrix metalloproteases (MMPs) are the proteolytic enzymes accountable for extracellular matrix (ECM) modification through their Zn2+-dependent catalytic activity. Among these, MMP-12 is one of the crucial MMPs that contributes to various disease states including different types of cancers and other major pathophysiological conditions including COPD, asthma, emphysema, skin diseases, arthritis, vascular diseases, and neurological disorders. The majority of the MMP-12 inhibitors should have three constitutional pharmacophoric features (i.e., a hydrophobic group to occupy the S1' pocket, a zinc-binding motif for chelating to the catalytic Zn2+ ion present at the catalytic site, and a flexible and hydrogen bond forming linker region between the S1' pocket substituent and the zinc chelating group for interacting with the catalytic and Ω-loop amino acid residues). This review mainly focuses on the various roles of MMP-12 in different diseases along with the structural comparison with other MMPs as well as promising and MMP-12-selective inhibitors and molecular modeling studies performed on MMP-12 inhibitors. Therefore, this review will provide comprehensive information to the researchers for designing effective and MMP-12-selective inhibitors for therapeutic advancement in the future.

In silico design, modelling and molecular mechanisms of Axl receptor tyrosine kinase inhibitors

A kinase domain from receptor tyrosine kinases (RTKs) regulate intracellular communications to control cellular metabolic activities. Some of the malignant cells have upregulated and overexpressed RTKs which are responsible for angiogenesis in many metastatic cancers. Axl RTK is present in most of the eukaryotic cells and all metastatic cancer cells have overexpressed Axl tyrosine kinase to trigger uncontrolled growth and angiogenesis in the malignant cells. The upregulated kinases can be inhibited in its active and inactive states in the presence of small organic molecule inhibitors. Kinase inhibitors have been discovered to arrest the signal transduction pathways in the malignant cells as a therapy and cure for cancer. In this work, small molecule databases were screened using the pharmacophore features of a macrocyclic inhibitor (7YS) taken as reference from the crystal structure of Axl kinase domain. Pharmacophore based virtual screening of small molecule libraries (CHEMBL32, ChemDiv, Chemspace, Mcule, MolProt, PubChem and Zinc), followed by molecular docking, molecular dynamics simulations, binding energies from MM-PBSA calculations and trajectory analysis as principal component analysis were studied. The molecular basis for the binding of macrocyclic inhibitor, ATP and seven screened hit molecules bound at Axl kinase domain in two different modes at catalytic and regulatory sites was analyzed.

Discovery of Novel Inhibitors Against Resistant Streptococcus pneumoniae MurF Enzyme using Phamracophore Modeling and QSAR Analysis

Main aim of the current study was to discover novel inhibitors against Streptococcus pneumoniae MurF enzyme using analogue based drug design. Pharmacophore mapping and 3D-QSAR analysis was performed on some previously synthesized and evaluated sulfonamide derivatives which are known to be potent inhibitors of penicillin resistant Streptococcus pneumoniae MurF receptor. 3D-QSAR study based on the principle of alignment of pharmacophoric features was performed on the same set of inhibitors using the PHASE module of Schrodinger suite. A five point pharmacophore, ADHRR, with one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic group and two aromatic rings yielded a statistically significant 3D-QSAR model with 0.96 as R2 value for three PLS components and good predictive correlation coefficients of Q2 = 0.8084, F = 140.6 and Pearson-R = 0.9157 for the test set with nine compounds. Thus, indicating good predictive power of the pharmacophore based 3D-QSAR model.

Identification of potential methyltransferase NSD2 enzymatic inhibitors through a multi-step structure-based drug design.

Reversing aberrant protein methylation levels is widely recognized as a key focus in cancer therapy. As an essential lysine methylation regulator, NSD2 (Nuclear receptor-binding SET Domain 2, also known as WHSC1/MMSET) regulates chromatin structural sparsity and DNA repair processes. Abnormal enhancement of NSD2 methylation activity (caused by NSD2 overexpression and point mutations) has been closely related to the initiation and development of various cancers and diseases. However, the lack of selective inhibitors hinders further therapeutic intervention and limits the exploration of its biological mechanism. Therefore, this study developed an integrated approach that includes binding feature pharmacophore modeling, gradient database screening of 120 million compounds, flexible docking, and molecular dynamic simulation. This approach was used to identify hit compounds targeting the substrate/coenzyme binding site of NSD2. Subsequently, 20 lead compounds were retrieved by using molecular docking analysis and ADMET prediction. Finally, MD simulations were performed to validate the binding stability of selected drug candidates. The findings indicated that these newly obtained compounds might be potent NSD2 inhibitors. We hope the integrated virtual screening approach will provide a valuable idea for discovering novel H3K36 methyltransferase inhibitors.

Expression of PPAR-γ TF by newly synthesized thiazolidine-2,4-diones to manage glycemic control: Insights from in silico, in vitro and experimental pharmacology in wistar rats.

In pursuit of novel antidiabetic agents to combat type II diabetes mellitus, our study focused on identifying pharmacophoric features responsible for PPAR-γ expression, a key regulator of glucose homeostasis and lipid metabolism. This goal was achieved through pharmacophore model generation and screening of rationally designed library of thiazolidine-2,4-dione hybrids (7a-7f). The top hits were synthesized, characterized, and evaluated for their in vitro and in vivo antidiabetic activities. Among these, compounds 7b and 7c emerged as promising candidates, exhibiting significant in vitro inhibitory activity against human pancreatic α-amylase (HPA) and human liver α-glucosidase (HLAG) enzymes, along with enhanced glucose uptake in L6 myotube cell lines. Specifically, compound 7b showed 29.04±1.13µM HPA inhibition, 34.21±1.16µg/mL HLAG inhibition, and 77.12±1.02% glucose uptake, while compound 7c displayed 28.35±1.01µM HPA inhibition, 26.21±1.17µM HLAG inhibition, and 78.54±0.54% glucose uptake. Mechanistic studies revealed a dose-dependent increase in PPAR-γ transcription factor expression, supported by molecular docking that showed favorable interactions with key residues TYR473, SER289, and HIE323. Molecular dynamics simulations confirmed the stability of these interactions, and MM/GBSA binding free energy calculations indicated potential for further optimization. In vivo studies in STZ-induced diabetic Wistar rats demonstrated significant improvements in glucose homeostasis, insulin sensitivity, and lipid metabolism, with a notable decrease in triglycerides and VLDL levels. Compound 7c also showed an improved pharmacokinetic profile with a half-life of 4.01h and an elimination rate constant of 0.325, compared to compound 7b. Both compounds enhanced glycogen content and antioxidant biomarkers, with a high safety profile (LD50 of 500mg/kg). Overall, compound 7c stands out as a promising lead for further development, with compound 7b also showing strong potential, providing valuable insights for future antidiabetic drug development efforts.

Unveiling novel type 1 inhibitors for targeting LIM kinase 2 (LIMK2) for cancer therapeutics: An integrative pharmacoinformatics approach

LIMK2 is crucial in regulating actin cytoskeleton dynamics, significantly contributing to cancer cell proliferation, invasion, and metastasis. Inhibitors like LIMKi3 effectively suppress LIMK2 kinase activity by directly affecting actin polymerization and preventing the formation of structures like filopodia and lamellipodia, which are typical of motile cancer cells. By modulating these actin dynamics, LIMKi3 inhibits cancer cell migration and invasion, reducing the potential for metastasis. Thus, this study aims to explore potential anti-cancer therapeutic LIMK2 inhibitors with properties resembling LIMKi3. Henceforth, molecular docking was utilized in this study to comprehend the ATP mimetic binding mode of LIMKi3, followed by Pharmacophore-based virtual screening to identify small molecules resembling LIMKi3. In addition, molecular dynamics simulations were performed to explore the dynamic behavior of LIMK2 and potential inhibitors. Further, network analysis and binding free energy calculations were implemented to comprehensively assess the interactions between the compounds and LIMK2. In molecular docking, LIMKi3 demonstrated an ATP mimetic hinge binding mode with hydrogen bonds at Ile408. Among the screened compounds (NCI300395, ChemDiv-8020–2508, and ChemDiv-7997–0024), three displayed "ADRH" pharmacophoric features like LIMKi3, with favorable ADMET properties, higher binding affinity, and significant hydrogen bond interactions at Ile408. LIMK2-inhibitor complexes showed lower RMSD than LIMK2-LIMKi3, indicating higher equilibrium by identified compounds. Protein-drug Complexes exhibited significant inter-domain correlation in N-lobe residues of LIMK2, including conserved β3, αC, and Hinge residues. Binding free energy analysis ranked LIMK2-NCI300395 highest, followed by LIMK2-ChemDiv-7997–0024 and LIMK2-ChemDiv-8020–2508, highlighting their potential as effective LIMK2-targeting compounds. Hence, this study emphasizes LIMKi3's significance and identifies potential candidates (NCI300395, ChemDiv-7997–0024, and ChemDiv-8020–2508) for developing cancer therapeutics targeting LIMK2. These findings open avenues for further investigations into the complex interplay between cytoskeletal dynamics and cancer progression.

Natural benzofuran derivatives as promising scaffold for alleviating Alzheimer symptoms: acetylcholinesterase inhibition, structure activity relationship and in silico studies

Three isolated natural benzofuran compounds 1a-c and four semi-synthesized benzofuran derivatives 2a,b and 3a,b were evaluated for their in vitro acetylcholinesterase inhibition assay. Most of the tested compounds showed moderate activity with IC50 ranged from 102.4 ± 5.72 µM to 565.75 ± 4.17 µM, the most potent compound was kellin 1a with IC50 102.4 ± 5.72 µM. The kellin derivatives 1a, 2a and 3a bearing additional methoxyl group showed more inhibition activity than its analogues of visnagin derivatives 1b,c, 2b and 3b. The in silico investigation on the seven benzofuran derivatives matched our in vitro acetylcholinesterase results and explains the similarity in structures between the benzofuran compounds and donepezil drug. khellin had the best pharmacophore features among the studied compounds, the best fit score 1.862 and best dock score −9.135. In addition, our in silico study showed clearly that compounds carrying additional hydrophobic group had more potent activity through matched more ligand features.

Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers

A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potency (IC50 = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). 7g was potent against liver cancer (HepG-2; IC50 = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). 7g surpassed NNGH against MMP-10 (IC50 = 0.205 μM) and MMP-13 (IC50 = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.

Targeting N-Methyl-lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery.

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. Overexpression or deregulation of KDM4 enzymes is associated with various cancers, altering chromatin structure and causing transcriptional dysfunction. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors. KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. Industrial and academic efforts in medicinal chemistry have identified numerous KDM4 inhibitors, primarily pan-KDM4 inhibitors, though they often lack selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non-chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature's chemical diversity to pursue more potent and selective KDM4 inhibitors.