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PubMed2001

Design and synthesis of celecoxib and rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere.

Celecoxib (13) and rofecoxib (17) analogues, in which the respective SO2NH2 and SO2Me hydrogen-bonding pharmacophores were replaced by a dipolar azido bioisosteric substituent, were investigated. Molecular modeling (docking) studies showed that the azido substituent of these two analogues (13, 17) was inserted deep into the secondary pocket of the human COX-2 binding site where it undergoes electrostatic interaction with Arg(513). The azido analogue of rofecoxib (17), the most potent and selective inhibitor of COX-2 (COX-1 IC(50) = 159.7 microM; COX-2 IC(50) = 0.196 microM; COX-2 selectivity index = 812), exhibited good oral antiinflammatory and analgesic activities.

Administration, Oral↗

PubMed2003

Novel estrogen receptor ligands based on an anthranylaldoxime structure: role of the phenol-type pseudocycle in the binding process.

The 3,4-diphenylsalicylaldoxime system 1 is an estrogen receptor (ER) ligand of unusual structure, having a hydrogen-bonded pseudocyclic A'-ring in place of the paradigmatic phenolic A-ring that is characteristic of most estrogens. We have investigated the role played by the pseudocycle A' in binding to the ER by preparing 3,4-diphenylbenzaldoxime (4), a compound that completely lacks this ring but still preserves all of the other features of the original molecule 1, as well as a series of 3,4-diphenylanthranylaldoximes (5a-c) in which the nature of the heteroatom participating in the formation of pseudoring A' has been changed from an oxygen (1) to a nitrogen that is either unsubstituted (5a) or substituted with small alkyl groups (a methyl in 5b, or an ethyl in 5c). The importance of hydrogen-bonded pseudocycle A' in the binding process was confirmed by the fact that benzaldoxime 4 showed a greatly reduced binding affinity compared to salicylaldoxime 1. Moreover, the binding affinity improved considerably when the A'-ring contained either an unsubstituted nitrogen (5a) or an N-Me group (5b). On the other hand, the N-Et-substituted anthranyl derivative 5c showed a marked drop in binding affinity. Molecular modeling docking studies on ERalpha confirmed that compounds 5a and 5b fit nicely in the ligand binding pocket, with an especially comfortable fit for the N-Me group of 5b in a small hydrophobic pocket surrounded by nonpolar residues. The limited size of this pocket does not allow accommodation of N-substituents larger than a methyl group, which is consistent with the low binding affinity of the N-Et compound 5c.

Benzene Derivatives↗

PubMed2005

Design and synthesis of (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes and (Z)-1-(4-azidophenyl)-1,2-diphenylalk-1-enes: novel inhibitors of cyclooxygenase-2 (COX-2) with anti-inflammatory and analgesic activity.

A group of novel (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 enzyme inhibition studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)oct-1-ene (8d) as a highly potent (IC50=0.03 microM), and an extremely selective [COX-2 SI (selectivity index)>3,333], COX-2 inhibitor that showed good anti-inflammatory (AI) activity (ID50=2.8 mg/kg). A molecular modeling (docking) study showed that the p-MeSO2NH group present in (Z)-8d inserts deep inside the 2 degrees-pocket of the COX-2 binding site, it undergoes a hydrophobic interaction with Ala516 and Gly519, and one of the O-atoms of the MeSO2 group participates in a weak hydrogen bonding interaction with the NH2 of Arg513 (distance= 3.85 angstroms). Similar in vitro COX-1/COX-2 enzyme inhibition studies showed that the azido compound 1-(4-azidophenyl)-1,2-diphenyloct-1-ene (9c) is also a potent and selective COX-2 inhibitor (COX-2 IC50=0.11 microM: SI>909) that exhibits good AI activity (ID50=5.0 mg/kg). A docking experiment to determine the orientation of (Z)-9c within the COX-2 binding site showed that the linear p-N3 group inserts into the COX-2 2 degrees-pocket, where it undergoes an ion-ion (electrostatic) interaction with Arg513. Structure-activity data acquired indicate that an olefin having either a C-1 p-MeSO2NH-phenyl, or a p-N3-phenyl, substituent, that is, cis to a C-2 unsubstituted phenyl substituent, in conjunction with C-1 unsubstituted phenyl and C-2 alkyl substituents, provides a novel template to design acyclic olefinic COX-2 inhibitors.

Alkenes↗

PubMed2006

Design and synthesis of new water-soluble tetrazolide derivatives of celecoxib and rofecoxib as selective cyclooxygenase-2 (COX-2) inhibitors.

In an attempt to prepare a new water-soluble, parenteral COX-2 inhibitor, rofecoxib (9) and celecoxib (13) analogues were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo anti-inflammatory activity. In this experiment, respective SO(2)Me and SO(2)NH(2) hydrogen-bonding pharmacophores were replaced by a tetrazole ring. Molecular modeling (docking) studies showed that the tetrazole ring of these two analogues (9 and 13) was inserted deep into the secondary pocket of the human COX-2 binding site where it undergoes electrostatic interaction with Arg(513). The rofecoxib (9) and celecoxib (13) analogues exhibited a high in vitro selectivity (9, COX-1 IC(50) = 3.8 nM; COX-2 IC(50) = 1.8 nM; SI = 2.11; 13, COX-1 IC(50) = 4.1 nM; COX-2 IC(50) = 1.9 nM; SI = 2.16) relative to the reference drug celecoxib (COX-1 IC(50) = 3.7 nM; COX-2 IC(50) = .2 nM; SI=1.68) and also showed high aqueous solubility at pH higher than 7 and good anti-inflammatory activity in a carrageenan-induced rat paw edema assay. However, 9 and 13 had no significant damage on gastric mucosa.

Animals↗

PubMed2007

Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay.

Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (IK) and fast transient K+ currents (IA). When applied externally, these six compounds preferentially blocked IK with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.

Animals↗

PubMed2000

Shape complementarity, binding-site dynamics, and transition state stabilization: a theoretical study of Diels-Alder catalysis by antibody 1E9.

Antibody 1E9 is a protein catalyst for the Diels-Alder reaction between tetrachlorothiophene dioxide and N-ethylmaleimide. Quantum mechanical calculations have been employed to study the 1E9-catalyzed Diels-Alder reaction in the gas phase. The transition states and intermediates were all determined at the B3LYP/6-31G*//HF/6-31G* level. The cycloaddition step is predicted to be rate-determining, and the endo reaction pathway is strongly favored. Binding of the reactants and the transition states to antibody 1E9 was investigated by docking and molecular dynamics simulations. The linear interaction energy (LIE) method was adopted to estimate the free energy barrier of the 1E9-catalyzed Diels-Alder reaction. The catalytic efficiency of antibody 1E9 is achieved by enthalpic stabilization of the transition state, near-perfect shape complementarity of the hydrophobic binding site for the transition state, and a strategically placed hydrogen-bonding interaction.

Antibodies, Catalytic↗

PubMed2004

Comparative analysis of putative agonist-binding modes in the human A1 adenosine receptor.

A recent study reported a model of the human A(1) adenosine receptor and its agonist binding site, proposing two putative binding modes in the same binding site for the natural agonist, adenosine. The present work investigates the flexibility of this binding site by exhaustive exploration with the natural agonist and with three other adenosine derivatives: N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and 5'-N-ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for agonists that would explain the role in the binding process of the different substitutions allowed at the 2, N6, and 5' positions of adenosine. This problem was addressed through docking simulations, molecular dynamics studies, and estimations of the ligand-binding free energy with both the AUTODOCK scoring function and the linear interaction energy (LIE) approach. The results point to a single receptor-binding position that explains the effects of the different chemical modifications on the adenosine derivatives considered here.

Adenosine↗

PubMed2002

1.3-A resolution structure of human glutathione S-transferase with S-hexyl glutathione bound reveals possible extended ligandin binding site.

Cytosolic glutathione S-transferases (GSTs) play a critical role in xenobiotic binding and metabolism, as well as in modulation of oxidative stress. Here, the high-resolution X-ray crystal structures of homodimeric human GSTA1-1 in the apo form and in complex with S-hexyl glutathione (two data sets) are reported at 1.8, 1.5, and 1.3A respectively. At this level of resolution, distinct conformations of the alkyl chain of S-hexyl glutathione are observed, reflecting the nonspecific nature of the hydrophobic substrate binding site (H-site). Also, an extensive network of ordered water, including 75 discrete solvent molecules, traverses the open subunit-subunit interface and connects the glutathione binding sites in each subunit. In the highest-resolution structure, three glycerol moieties lie within this network and directly connect the amino termini of the glutathione molecules. A search for ligand binding sites with the docking program Molecular Operating Environment identified the ordered water network binding site, lined mainly with hydrophobic residues, suggesting an extended ligand binding surface for nonsubstrate ligands, the so-called ligandin site. Finally, detailed comparison of the structures reported here with previously published X-ray structures reveal a possible reaction coordinate for ligand-dependent conformational changes in the active site and the C-terminus.

Apoenzymes↗

PubMed2004

Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site.

The present work describes the building of a human A(1) adenosine receptor (hA(1)AR) model, based on the X-ray crystal structure of bovine rhodopsin, and its use as a basis for the investigation of some important structural characteristics of the receptor. One of the issues investigated was the protonation position of two histidine residues known to influence ligand binding, with protonation of His251 (6.52) in epsilon position and His278 (7.43) in delta position showing the best agreement with experimental evidence. The model was also used to study the position and structural role of water molecules present in the helical bundle. Finally, the binding site location and the ligand docking were investigated using an objective strategy. A suitable site for the binding of the ribose moiety of adenosine was first postulated and further confirmed by means of a novel chemometric strategy based on GRIND descriptors. Using this position as an anchor point, the binding of adenosine was studied by docking and molecular dynamics simulations obtaining two putative binding positions in good agreement with experimental data.

Adenosine↗

PubMed2026

Identification and functional validation of glutathione S-transferase genes involved in detoxification of sulfoxaflor, afidopyropen and lambda-cyhalothrin in Aphis glycines.

BACKGROUND: Glutathione S-transferases (GSTs) play important roles in the detoxification of insecticides in insects. However, genome-wide identification and functional characterization of the GST gene family in the soybean aphid Aphis glycines have not been performed. RESULTS: A total of 17 AgGST genes were identified in the A. glycines genome and classified into five classes. Phylogenetic analysis and chromosomal mapping showed that delta and epsilon class genes experienced significant expansion. Exposure to LC₅₀ concentrations of sulfoxaflor, afidopyropen and lambda-cyhalothrin strongly induced several AgGST genes with AgGSTd5, AgGSTd6 and AgGSTe2 displaying the highest expression levels. RNA interference of AgGSTd5 significantly increased aphid mortality following exposure to all three insecticides. Knockdown of AgGSTd6 significantly elevated mortality under sulfoxaflor, while knockdown of AgGSTe2 significantly increased mortality under both sulfoxaflor and lambda-cyhalothrin. In contrast, silencing of AgGSTt1 and AgGSTt2 showed no significant effect on aphid mortality under the tested insecticides. CONCLUSION: This study provides comprehensive characterization of the GST gene family in A. glycines and demonstrates that AgGSTd5 plays a central role in the detoxification of sulfoxaflor, afidopyropen and lambda-cyhalothrin, while AgGSTd6 and AgGSTe2 contribute to tolerance against specific insecticides among the three compounds. These genes represent promising molecular targets for monitoring insecticide detoxification responses and for the development of strategies based on GST inhibitors to enhance insecticide efficacy in integrated pest management. © 2026 Society of Chemical Industry.

Animals↗

PubMed1996

Molecular machinery mediating vesicle budding, docking and fusion.

A general machinery buds and fuses transport vesicles which connect intracellular compartments with each other and allow communication with the extracellular environment. Cytoplasmic coat proteins deform membranes to bud vesicles and interact directly or indirectly with cargo molecules. Compartment-specific SNAREs (SNAP receptors) on vesicles and target membranes dock vesicles and provide a scaffolding for the general fusion machinery to initiate lipid bilayer fusion.

Capsid↗

PubMed1999

Catechol(amine)s as probes of lactoperoxidase catalytic site structure: spectroscopic and modeling studies.

Binding affinities to lactoperoxidase (LPO) of a homologous series of substituted catechol(amine)s [such as catechol, 4-methylcatechol, 3,4-dihydroxybenzoic acid, 3,4-dihydroxyphenylacetic acid, 3-(3,4-dihydroxyphenyl)propionic acid; dopamine, noradrenaline, adrenaline; L-3,4-dihydroxyphenylalanine] were studied by UV-visible spectroscopy and docking simulations. Dissociation constant (Kd) values were calculated by direct fitting of the experimental data and fall in a range of 3-95 mM. Thermodynamic parameters are comparable with those reported for the interaction of LPO with p-substituted phenols, suggesting a similar general mode of binding. Furthermore, the relative contributions to binding energy, described by the unimolecular constant Ku, show that interaction between protein and ligands originates from a relatively large number of groups. Docking and molecular dynamics simulations, in agreement with experimental evidence, predict that the substrate is localized into the access channel in the vicinity of heme distal pocket. This channel is characterized by a hydrophobic patch (six Phe residues) and by a charged contribution (two Glu and one His residues). All of the substrates, except caffeic acid, may approach the protein active site. Positively charged Arg372 acts as a gate above the heme distal pocket and seems to address substrate orientation in relation to the side-chain terminal group.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2026

Mapping the Molecular Evolution and Role of Wild Rice GLYIII Protein-Encoding Genes in Abiotic Stress Response.

To address the need for sustainable food production amid rapid global climate change, developing rice varieties that grow optimally even under harsh conditions is essential. An effective approach in this direction would be to harness the stress resilience traits of the crop wild relatives (CWRs) of rice. Among the various crucial stress-responsive genes, the Glyoxalase III (GLYIII) gene family is of utmost importance for its ability to detoxify the toxic glycolytic byproduct, methylglyoxal (MG), in a less energy-intensive, single-step process, as well as for its multifaceted cytoprotective role. In our study, a comprehensive genome-wide search across the Oryza genus revealed that GLYIII genes are conserved across wild rice genotypes. Their number has expanded during domestication, driven by gene duplications. Interestingly, only a few orthologous pairs showed positive selection, suggesting that the functions of most others need to be constrained and or conserved.We found that higher GLYIII activity, Total Antioxidant Capacity, endogenous glutathione (GSH) levels, and free radical scavenging activity contributes to the stress resilience of wild rices O. punctata, O. meridionalis, and O. nivara, in addition to other factors. , , . , . Our qRT-PCR analysis revealed differential expression of the OpGLYIII, OmGLYIII, and OnGLYIII genes across different developmental stages and in response to various abiotic stresses. Furthermore, we report that wild rice GLYIII proteins, specifically OpGLYIII-3, OmGLYIII-3, and OnGLYIII-5, exhibit high catalytic efficiency over a broad pH range and at higher temperatures under in vitro assay conditions. Overexpression of these proteins was found to impart substantial stress resilience to the transformed E. coli cells. These findings collectively suggest that GLYIII proteins constitute a key component of the abiotic stress response machinery in wild rice.

Oryza↗

PubMed2004

Homology modeling, force field design, and free energy simulation studies to optimize the activities of histone deacetylase inhibitors.

As an effort to develop therapeutics for cancer treatments, a number of effective histone deacetylase inhibitors with structural diversity have been discovered. To gain insight into optimizing the activity of an identified lead compound, a computational protocol sequentially involving homology modeling, docking experiments, molecular dynamics simulation, and free energy perturbation calculations was applied for rationalizing the relative activities of known histone deacetylase inhibitors. With the newly developed force field parameters for the coordination environment of the catalytic zinc ion in hand, the computational strategy proved to be successful in predicting the rank orders for 12 derivatives of three hydroxamate-based inhibitor scaffolds with indole amide, pyrrole, and sulfonamide moieties. The results showed that the free energy of an inhibitor in aqueous solution should be an important factor in determining the binding free energy. Hence, in order to enhance the inhibitory activity by adding or substituting a chemical group, the increased stabilization in solution due to the structural changes must be overcome by a stronger enzyme-inhibitor interaction. It was also found that to optimize inhibitor potency, the hydrophobic head of an inhibitor should be elongated or enlarged so that it can interact with Pro29 and His28 that are components of the flexible loop at the top of the active site.

Amino Acid Sequence↗

PubMed2005

Modelling the interaction of catecholamines with the alpha 1A adrenoceptor towards a ligand-induced receptor structure.

Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human alpha1A adrenoceptor. Analysis of agonist/alpha1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.

Adrenergic alpha-1 Receptor Agonists↗

PubMed2026

Structure-based drug design of small-molecule c-Myc G-quadruplex binders.

The c-Myc oncogene is crucial in tumorigenesis. Although it is a promising therapeutic target, its protein lacks a conventional drug-binding pocket, making it traditionally "undruggable". Recent studies show that the c-Myc promoter can form a G-quadruplex (G4) structure, which suppresses transcription and offers a new strategy for indirect inhibition. In this study, structure-based virtual screening was performed using the c-Myc G4 crystal structure to screen the ChemDiv compound library, aiming to identify small molecules that bind to the G4 structure. Candidate compounds were evaluated in preliminary in vitro assays for biological activity. The results showed that Y502-3888 binds to the c-Myc G4 and downregulates c-Myc expression at both mRNA and protein levels. Collectively, these findings support the potential of Y502-3888 as a c-Myc G4 binder for the treatment of multiple myeloma (MM), providing a foundation for future development of anticancer agents targeting the c-Myc G4.

G-Quadruplexes↗

PubMed2026

Identification and validation of natural dengue virus NS1 inhibitors with promising antiviral potential.

Dengue infection remains a major global public health challenge, with no specific antiviral therapy currently available. The dengue virus non-structural protein 1 (NS1) exists in both intracellular and secreted forms playing a pivotal role in viral replication, immune evasion, and pathogenesis, particularly by contributing to endothelial disruption and vascular leakage during severe disease, thereby making it a promising therapeutic target. In silico screening identified berberine, betulinic acid, and ursolic acid as top candidates, exhibiting high binding affinities and stable interactions within the NS1 binding pocket. These computational predictions were further validated by biophysical assays, which demonstrated strong and specific binding interactions between the purified NS1 protein and the selected compounds. All three compounds significantly reduced viral genome levels, with the highest inhibition observed for berberine (60%), and followed by betulinic acid (40%) and ursolic acid (28%). Consistently, berberine showed the most potent inhibition of both intracellular and extracellular NS1. Overall, these findings highlight the inhibitory potential of natural compounds against DENV NS1 and provide a strong foundation for the development of NS1-targeted antivirals as a novel therapeutic strategy against dengue infection.

Antiviral Agents↗

PubMed2026

Integrated bulk and single-cell RNA sequencing reveals a prognostic neuro-mimicry signature in papillary thyroid carcinoma.

BACKGROUND: Cancer cells can acquire neuron-like characteristics ("neural mimicry") to promote progression. However, the role of specific ion channel genes in Papillary Thyroid Carcinoma (PTC) and their clinical significance remains unclear. METHODS: We included transcriptomic data from 521 PTC patients in the TCGA cohort. A neuron-specific gene set was used to screen for potential targets. We constructed a prognostic model using LASSO logistic regression. To verify the cellular origin of the signature, we performed single-cell RNA sequencing (scRNA-seq) analysis on the GSE184362 dataset. RESULTS: We established an 8-gene signature involving KCNN4, KCNN1, KCNT2, SNAP25, KCNK16, GABRG1, GABRG2, and GABRB2. The model demonstrated good predictive performance for lymph node metastasis, with an AUC of 0.721 (95% CI 0.677-0.765). Single-cell analysis of seven integrated tumor samples (N = 65,744 cells) confirmed that GABRB2 was specifically enriched in malignant thyrocytes (EPCAM+/KRT18+) at 200-fold higher detection rates than immune cells (20.0% vs. 0.1%, P ≈ 0), supporting tumor-intrinsic neural mimicry. High-risk patients showed immunosuppressive features with altered immune cell infiltration patterns. CONCLUSION: This study identifies a malignant cell-intrinsic signature for predicting PTC prognosis. Validated by single-cell data, our findings suggest that targeting ion channels may represent a potential therapeutic strategy for modulating neuro-immune interactions in thyroid cancer, pending experimental validation.

GABRB2↗