Molecular Diversity最新文献

Glycogen synthase kinase-3β (GSK-3β) has emerged as a crucial target due to its substantial contribution in various cellular processes. Dysfunctional GSK-3β activity can lead to ion channel disturbances, sustain abnormal excitability, and contribute to the pathogenesis of epilepsy and other GSK-3β-related disorders. A set of 82 pyrazole analogs was utilized to study its structural features using a three-dimensional quantitative structure-activity relationship (3D-QSAR), virtual screening, molecular docking, and molecular dynamics. The QSAR model, validated using internal and external methods, demonstrated robustness with a high correlation coefficient r²_training = 0.99, cross-validation coefficient q² = 0.79, r²_test = 0.69, and r²_external = 0.74. The "Average of Actives" in the Activity Atlas model identified 17 molecules as active. Subsequent pharmacophore-based virtual screening of 17 actives yielded 70 compounds, which were selected as the prediction set to determine the potential GSK-3β inhibitors. Docking studies pinpointed compound P66 as the promising lead compound, with a docking score of - 10.555 kcal/mol. These findings were further supported by electrostatic potential (ESP), electrostatic complementarity (EC), and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analyses. Furthermore, a 500 ns molecular dynamics (MD) simulation confirmed the structural and conformational stability of the lead complex throughout the simulation period. As a result, this study suggests that compound P66 holds the potential to be a potent lead candidate for the inhibition of GSK-3β, offering a novel therapeutic approach for GSK-3β related disorders, including epilepsy.

The present study employed an integrated transcriptome and interactome-based analyses to identify key proteins and pathways associated with Acinetobacter baumannii infection towards the development of novel therapeutics against this pathogen. Transcriptome analysis of A.baumannii strains (ATCC 17978 and AbH12O-A2) identified 253 and 619 differentially expressed genes (DEGs), respectively. These genes were involved in essential molecular functions, including DNA binding, metal ion binding, and oxidoreductase activity. The centrality and module analyses of these identified DEGs had shortlisted 27 and 41 hub proteins, which were central to the ATCC 17978 and AbH12O-A2 networks, and essential for bacterial survival. Significantly, three proteins (SecA, glutathione synthase, and aromatic-amino-acid transaminase) from the ATCC 17978 strain and seven proteins (ATP synthase subunit alpha, translation initiation factor IF-2, SecY, elongation factors G, Tu, and Ts, and tRNA guanine-N1-methyltransferase) from the AbH12O-A2 strain showed interactions with human proteins, identified through host-pathogen interaction (HPI) analysis of hub proteins (referred as hub-HPI proteins). These proteins were observed to participate in vital pathways, including glutathione metabolism, secondary metabolite biosynthesis and quorum sensing. Targeting these hub-HPI proteins through novel therapeutic strategies holds the potential to disrupt the critical bacterial pathways, thereby controlling A. baumannii infections. Furthermore, their localization analysis indicated that nine proteins were cytoplasmic and one was membrane protein. Among them, six were druggable and four were novel proteins. Overall, this comprehensive study provides valuable insights into the crucial proteins and pathways involved during A. baumannii infection, and offers potential therapeutic targets for designing novel antimicrobial agents to tackle the pathogen.

Virus assembly, budding, or surface proteins play important roles such as viral attachment to cells, fusion, and entry into cells. The present study aimed to identify potential antigenic proteins and epitopes that could be used to develop a vaccine or diagnostic assay against the Monkeypox virus (MPXV) which may cause a potential epidemic. To do this, 39 MPXV proteins (including assembly, budding, and surface proteins) were analyzed using an in silico approach. Of these 39 proteins, the F5L virus protein was found to be the best vaccine candidate due to its signal peptide properties, negative GRAVY value, low transmembrane helix content, moderate aliphatic index, large molecular weight, long-estimated half-life, beta wrap motifs, and being stable, soluble, and containing non-allergic features. Moreover, the F5L protein exhibited alpha-helical secondary structures, making it a potential "structural antigen" recognized by antibodies. The other viral protein candidates were A9 and A43, but A9 lacked beta wrap motifs, while A43 had a positive GRAVY value and was insoluble. These two proteins were not as suitable candidates as the F5L protein. The KRVNISLTCL epitope from the F5L protein demonstrated the highest antigen score (2.4684) for MHC-I, while the GRFGYVPYVGYKCI epitope from the A9 protein exhibited the highest antigenicity (1.754) for MHC-II. Both epitopes met the criteria for high antigenicity, non-toxicity, solubility, non-allergenicity, and the presence of cleavage sites. Molecular docking and dynamics (MD) simulations further validated their potential, revealing stable and energetically favorable interactions with MHC molecules. The immunogenicity assessment showed that GRFGYVPYVGYKCI could strongly induce immune responses through both IFN-γ and IL-4 pathways, suggesting its capacity to provoke a balanced Th1 and Th2 response. In contrast, KRVNISLTCL exhibited limited immunostimulatory potential. Overall, these findings lay the groundwork for future vaccine development, indicating that F5L, particularly the GRFGYVPYVGYKCI epitope, may serve as an effective candidate for peptide-based vaccine design against MPXV.

Efficient synthesis of novel dimethyldihydropyrimido[4,5-b]quinolones via three-component condensation of barbituric acid, arylaldehydes, and 3,4-dimethylaniline catalyzed by Fe₃O₄@SiO₂@[Aminoglycol][Formate] as a new superparamagnetic nanocatalyst and [Aminoglycol][Formate] as a novel ionic liquid catalyst was described. The new heterogeneous nanocatalyst was characterized by FE-SEM, XRD, FT-IR, TGA-DTG, and VSM techniques. The new ionic liquid was characterized by ¹³CNMR, ¹HNMR, and FT-IR techniques. The present work has advantages, such as excellent yields, short reaction times, environmentally friendly protocol, easy separation, and purification of products. The catalysts kept its catalytic properties after even five recoverability and reusability.

Nicotinamidase/PncA is a member of the hydrolase enzyme family, catalyzing the de-amidation of nicotinamide (NM) to nicotinic acid (NA) via salvage pathway. Products are fed into Preiss-Handler pathway for NAD⁺ biosynthesis which is an important enzyme cofactor and crucial for redox balance in microorganisms. Pathogens like methicillin-resistant Staphylococcus aureus (MRSA) are NAD⁺ auxotroph and rely on their host environment for NAD⁺ precursors to synthesize NAD⁺. Mutations in nicotinamidase/PncA have been reported to be associated with resistance to pyrazinamide (PZA), a front-line anti-tubercular drug, underlying its importance as an important link in NAD⁺ biosynthesis network in pathogenic organisms such as MRSA. The conserved features of PncA and essentiality of salvage route in MRSA and the absence of this enzyme in humans and other eukaryotes are attractive options to explore therapeutics against this target. In this work, we have screened novel substrate analogs from the PubChem database using virtual screening approaches employing fingerprint tanimoto-based 2D similarity search against Staphylococcus aureus PncA (SaPncA). Identified compounds were further assessed using molecular dynamics simulations to investigate conformational stability and structural integrity. We propose two analogs, namely L28 and L33 with greater stability, favorable binding and strong binding free energies in MM-PBSA calculations. The strategy could provide an important clue in developing similar compound scaffolds as potent drug-like molecules against MRSA and other pathogenic species harboring this enzyme. Smaller scaffolds of these molecules could be attractive options for fragment-based derivatization for inhibitor discovery.

Anaplastic lymphoma kinase (ALK) plays a critical role in the development of various cancers. In this study, the dataset of 1810 collected inhibitors were divided into a training set and a test set by the self-organizing map (SOM) and random method, respectively. We developed 32 classification models using Support Vector Machines (SVM), Decision Trees (DT), Random Forests (RF), and Extreme Gradient Boosting (XGBoost) to distinguish between highly and weakly active ALK inhibitors, with the inhibitors represented by MACCS and ECFP4 fingerprints. Model 7D which was built by the RF algorithm using training set 1/test set 1 divided by the SOM method, provided the best performance with a prediction accuracy of 90.97% and a Matthews correlation coefficient (MCC) value of 0.79 on the test set. We clustered the 1810 inhibitors into 10 subsets by K-Means algorithm to find out the structural characteristics of highly active ALK inhibitors. The main scaffolds of highly active ALK inhibitors were also analyzed based on ECFP4 fingerprints. It was found that some substructures have a significant effect on high activity, such as 2,4-diarylaminopyrimidine analogues, pyrrolo[2,1-f][1,2,4]triazin, indolo[2,3-b]quinoline-11-one, benzo[d]imidazol and pyrrolo[2,3-b]pyridine. In addition, the subsets were summarized into several clusters, among which four clusters showed a significant relationship with ALK inhibitory activity. Finally, Shapley additive explanations (SHAP) was also used to explain the influence of modeling features on model prediction results. The SHAP results indicated that our models can well reflect the structural features of ALK inhibitors.

As another part continue for our previous study, variable substituted pyrazoles bearing sulfamoylphenyl moiety were synthesized and screened against two cancer related human carbonic anhydrase (hCA) isoforms and acetazolamide (AAZ) used as a reference standard. Some compounds as 4e and 6c manifested a promising inhibitory activity against both isoforms (K_I = 0.072, 0.081 and 0.073, 0.095 µM), respectively. While others as 4a and 5e showed inhibitory activity against hCA IX only (K_I = 0.062, 0.04 µM) or against hCA XII only as compound 5b (K_I = 0.106 µM) compared to AAZ (K_I = 0.065, 0.046 µM), respectively. Also, the anticancer efficacy against 60 cancer cell lines for the target compounds was assessed, and the most promising ones were 4d and 5a-d. Further investigation of the anticancer activity of 5b on MCF-7 cell line explored (IC₅₀ = 5.21 µM) compared to doxorubicin (IC₅₀ = 11.58 µM). Moreover, compound 5b was exposed to cell cycle analysis and apoptotic assay on MCF-7 breast cancer cell line under both normal and hypoxic conditions at its IC₅₀ concentration with elevation of total apoptotic cells % in MCF-7 relative to the control cells; respectively. Finally, molecular modelling simulations rationalized the in vitro testing results.

1,2,3-triazole is a vital structural motif of various drugs and therapeutic leads, as well as a linker for bioconjugation and molecular recognition. Cu-catalysed click cycloaddition of azides with terminal alkynes (CuAAc) is an important reaction to construct the triazole core. In recent years, various decarboxylative click strategies utilizing alkynoic acids as stable surrogates for low boiling or gaseous alkynes have been developed. For instance, propiolic acid, which is easy to transport, is a safe alternative for flammable gaseous acetylene. In this review article, we have covered the recent development in the decarboxylative click cycloaddition of alkynoic acids with azides leading to the synthesis of diversely substituted triazoles, including monosubstituted, 1,4-disubstituted and fully substituted 1,2,3-triazoles. Various aspects such as mechanistic insights and optimization conditions/role of catalyst are highlighted.

A novel series of cyanopyridines 7a-j were synthesized via a one-pot multicomponent reaction of arylidene 4 with ammonium acetate 5 and respective methylaryl/heterylketones 6a-j in ethanol using vanillin as a natural starting material. Moreover, the regioselective alkylation reaction was studied by the treatment of cyanopyridines 7a-f and 7j with CH₃I in the presence of K₂CO₃ in DMF to afford O-methylcyanopyridines 8a-g (major) and N-methylcyanopyridines 9a-g (minor), whereas bipyridine 7h gave bipyridinium iodide salt 10. All of the designed cyanopyridines were evaluated as anti-breast cancer (MCF-7) cell lines via PIM Kinase inhibitory activity, and the results displayed that some of them showed high activities, especially compounds 7h and 8f, which showed excellent activities against MCF-7 with IC₅₀ values of 1.89 and 1.69 μM, respectively, more potent than the reference drug doxorubicin. Mechanistically, compounds 7h and 8f exhibited strong in vitro PIM-1 kinase inhibitory activity with an IC₅₀ of 0.281 and 0.58 μM, respectively, compared to the reference staurosporine. Moreover, compound 7h arrested the tumor cells at the S phase and caused cell death mainly by inducing early and late apoptosis. Molecular docking studies against PIM-1 revealed good binding modes of the synthesized compound and showed agreement with the biological results.

A series of rationally designed benzothiazole-derived thioacetamides was synthesized and investigated for monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) inhibition properties. The tested compounds 18-31 inhibited MAO-A and MAO-B in the micromolar to nanomolar range and AChE in the submicromolar range. Compound 28 was identified as the most potent MAO-A inhibitor with an IC₅₀ = 0.030 ± 0.008 µM, whereas compound 30 showed the highest potency towards MAO-B and AChE with IC₅₀ values of 0.015 ± 0.007 µM and 0.114 ± 0.003 µM, respectively. Further, compound 30 inhibited BChE at an IC₅₀ value of 4.125 ± 0.143 µM. Among all screened molecules, compound 30 emerged as the lead dual MAO-B and AChE inhibitor that blocked these enzymes in a competitive-reversible and mixed-reversible mode, respectively. Selected compounds have displayed iron-chelation and antioxidant properties. Further, computational assessment of ligand binding affinity and pharmacokinetic parameters of all new compounds and molecular dynamic simulation of compound 30 with MAO-B and AChE were carried out to understand ligand efficiency, pharmacokinetic, and virtual molecular interaction profile, respectively. The in silico ADMET prediction studies revealed a few undesired pharmacokinetic attributes of our compounds. The attempted virtual lead-based library synthesis and subsequent biological investigation produced a new benzothiazole-bearing dual MAO-B and AChE inhibitor as a prospective MTDL candidate for treating neurological disorders.