Molecular Diversity最新文献

The universal two-stage synthesis of 1-alkyl-4-methyl- and 1,3,4-trialkylsubstituted semiselenoglycolurils was realized on the basis of a range of semithioglycolurils, which were S-methylated to isothiouronium salts, followed by the interaction of the salts with NaHSe generated in situ from Se and NaBH₄. The resulting semiselenoglycolurils were tested as antimicrobials and exhibited selective inhibition of filamentous fungi. A broad comparison with previously reported analogs revealed their fungistatic mode of action and highlighted the significant influence of steric hindrance of the selenium atom on antifungal activity. These findings suggest that semiselenoglycolurils may possess a novel antifungal mechanism, warranting further detailed investigation of their molecular targets. In addition, 1,3,4-trialkylsemiselenoglycolurils effectively inhibit the growth of phytopathogenic fungi.

In recent years, the number of patients with ALK-positive NSCLC has increased, along with the emergence of various resistance mutations. To address the resistance issues caused by ALK mutations, this study used Crizotinib as the lead compound and modified its side chain to design and synthesize a series of compounds containing thiadiazole structures. The compounds were evaluated through tyrosine kinase inhibition assays and cellular experiments. The results show that compound B11 exhibits strong cytotoxic activity against the NSCLC NCI-H2228 cell line. Moreover, B11 demonstrates a dose-dependent effect, inhibiting NCI-H2228 cell viability, inducing G0/G1-phase cell cycle arrest, and promoting cell death. More importantly, compound B11 overcomes the resistance caused by the ALK^G1202R mutation. Ultimately, compound B11, which contains a thiadiazole structure, shows promising activity (ALK^L1196M IC₅₀ = 5.57 nM; ALK^wt IC₅₀ = 9.19 nM; ALK^G1202R IC₅₀ = 15.6 nM).

Activity of acetylcholinesterase (AChE) enzyme elevation has been frequently observed in Alzheimer's disease (AD) and plays a key role in disease progression. Therefore, its inhibition is considered a crucial therapeutic step in the management of cognitive defects associated with AD. In this study, we screened a library of fungal metabolites using molecular docking, molecular dynamics, and PCA to identify metabolic compounds that effectively worked against AChE. An extensive database of 19,667 fungal metabolites was methodically filtered to identify compounds with drug-like properties that are suitable for neurological disorders. Of all metabolites, only four compounds inhibited AChE better than donepezil. Mangrovamide F was the most effective against AChE, followed by Libertellenone M, Tricholopardin A, and Aspeterreurone A (ΔG: -12.6 ± 0.2, -12.3 ± 0.2, -12.2 ± 0.2, -11.8 ± 0.1 kcal/mol, respectively). Aspeterreurone A had the highest LD₅₀ dose (39,800 mg/kg), followed by Tricholopardin A (8350 mg/kg), Mangrovamide F (707 mg/kg), and Libertellenone M (190 mg/kg). Over the course of the 200-ns simulation, the protein in the AChE-fungal metabolite complexes stabilized and fluctuated within the permissible range. The most important residue, TRP86, in the AChE protein often interacts with all the best-hit ligands primarily through hydrophobic interactions, for the longest period with Libertellenone M, followed by Tricholopardin A, Mangrovamide F, Donepezil, and Aspeterreurone A. According to our PCA data, Mangrovamide F (44.61%) had the highest eigenvalue rank, followed by Libertellenone M (27.49%), Aspeterreurone A (23%), and Tricholopardin A (20.02%). Mangrovamide F and Tricholopardin A were found to be the best inhibitors of AChE enzyme with acceptable LD₅₀ and have less toxicity. Further in vitro and in vivo works regarding the therapeutic effects of these fungal compounds could elaborate our findings.

The increasing prevalence of Acinetobacter baumannii infections and its severity demand the acute necessity for innovative therapeutic targets against it. This study employs comprehensive pangenome analysis to investigate 124 A. baumannii multidrug-resistant strains, to determine the most promising therapeutic targets derived from its core genome. Nucleotide diversity analysis of core and variable gene clusters identified key polymorphisms, suggesting significant evolutionary adaptation. Our findings revealed significant presence/absence variation (PAV) in resistance genes across strains, with 97 antimicrobial drug resistance genes identified. Two gene clusters, cluster-288 and cluster-566, harbored resistance-related genes encoding for beta-lactamase and multidrug efflux pump, respectively, were identified from the core genome that plays a pivotal role in conferring multidrug resistance. The functional enrichment analysis of these gene clusters highlighted key proteins, such as penicillin-binding proteins and outer membrane efflux proteins, as potential targets for drug design. Furthermore, we analyzed the physicochemical properties, virulence potential, active site prediction, and predicted conserved motifs. Structural predictions via 3D modeling and molecular dynamics simulations revealed high stability of key proteins, with RMSD values of 0.52 nm for outer membrane channel subunit AdeK and 0.85 nm for beta-lactamase, suggesting these proteins' potential as novel drug targets and their structural integrity under physiological conditions. Principal component analysis (PCA) highlighted distinct motion patterns within these proteins, providing insights into their functional dynamics. This research contributes to ongoing efforts to combat antibiotic resistance through innovative approaches in drug design and therapeutic interventions.

Leishmaniasis, a major neglected tropical disease (NTD), affects millions of people globally. Current treatments are plagued by infection relapse, high toxicity, and lengthy regimens. A contemporary study investigated the 2-aminobenzimidazole scaffold for leishmanicidal activity but it was found to be associated with poor exposure and lack of efficacy in vivo. This inspired us to develop a QSAR model of leishmanicidal activity leveraging the reported in vivo leishmanicidal activity data toward Leishmania infantum. Interpretable 2D molecular descriptors were employed so that the key leishmanicidal structural features could be utilized to develop the novel molecules. The QSAR model highlighted key structural features associated with leishmanicidal activity, including hydrophobicity, aromatic ring, hydrogen bond acceptor/donor, as well as hetero-atoms (nitrogen, fluorine, etc.) that enhance activity. Various categories of drugs from DrugBank were screened using the developed QSAR model, followed by inverse docking against the putative protein targets for leishmaniasis, to identify the plausible target of the parent leads. QSAR-guided structural modifications were undertaken to generate potential analogs of the top five parent leads. The analogs were checked for their ADMET profiles, and the protein-ligand interactions stability of the top candidates (DB03231-A6 and DB12269-A4) was assessed by 300 ns molecular dynamics simulation. Free energy landscapes (FEL) of the apo and bound target receptor were constructed to further streamline the prioritized analogs. Upon cumulative retrospection, an analog of DB12269 (N-{5-[2-amino-4-fluro-7-(1-hydroxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-4,6-difluoropyrid-3yl}-2-(5-chloropyrazin-2-yl)acetamide) is proposed for further wet lab validation studies for prospective application against leishmaniasis.

Hospital-acquired infections (HAIs) caused by viral, bacterial, and fungal pathogens have resulted in numerous deaths all over the world. Klebsiella pneumoniae (Kp) is a drug-resistant Gram-negative bacterium responsible for HAIs. Aspartate β-semialdehyde dehydrogenase (ASADH) enzyme is crucial for the survival of Kp since it is involved in the biosynthetic pathway responsible for the production of essential amino acids and important metabolites. This pathway is absent in mammals and hence design of inhibitors for Kp ASADH becomes a good strategy for the treatment of HAIs. In this study, computational methodologies were employed to design inhibitors targeting Kp ASADH. Key active site residues were identified through the analysis of binding interactions with two established lead compounds, 4-nitro-2-phosphonobenzoic acid and (S)-methyl cysteine sulfoxide. A virtual screening of compounds from the NCI Diversity Database was conducted using molecular docking within the active site in the presence of coenzyme NADPH. Drug-like properties of the identified hit compounds were subsequently evaluated. These molecules were further validated using molecular dynamics simulations to assess their structural stability. The finalized hit compounds underwent additional stability assessments through normal mode analysis, mechanical stiffness evaluation, principal component analysis, and binding energy calculations using MM/GBSA. ADMET profiles of the final compounds were examined.

Porphyrins and metalloporphyrins are emerging as versatile platforms for advanced drug delivery due to their unique structural, photophysical, and coordination properties. These macrocyclic compounds, known for their chemical stability and capacity to chelate various metal ions, address critical challenges in drug delivery, including poor solubility, non-specific toxicity, and limited control over drug release. This review explores synthetic strategies for porphyrins and their metal complexes, including classical and green methods, and highlights their therapeutic applications through diverse nanocarrier systems, such as gold nanoparticles, cyclodextrin conjugates, mesoporous silica, liposomes, and metal-organic frameworks. These systems offer stimuli-responsive, targeted, and synergistic therapeutic functionalities-especially in cancer therapy-by combining chemotherapy with photodynamic or sonodynamic modalities. Despite their promise, limitations persist, including scalability issues, potential metal toxicity, and insufficient long-term biocompatibility data. The review outlines future directions, advocating for AI-driven design, sustainable synthesis, and expanded applications beyond oncology, emphasizing the need for systematic comparative studies and clinical translation efforts.

To uncover novel inhibitors of Werner (WRN) helicase, this study adopted the scaffold-hopping strategy to design and synthesize 24 novel 2-amino-4-(trifluoromethyl)pyrimidine derivatives. The MTT assay was employed to evaluate the anticancer activity of target compounds against microsatellite instability-high (MSI-H) cell lines (HCT116 and LNCaP) and microsatellite stability (MSS) cell lines (SW620 and PC3). Some compounds demonstrated significant inhibitory activity against all four cancer cell lines. Specifically, compounds 11c, 11f, 11 g, 11 h, and 11 l exhibited greater inhibitory effect toward MSI-H cells (HCT116 and LNCaP) compared to MSS cells (SW620 and PC3). The most active compound 11 g exhibited excellent cellular selectivity, with IC₅₀ values of 1.52 and 1.72 μM against MSI-H cell lines (HCT116 and LNCaP), respectively, while the IC₅₀ values of 11 g against MSS cell lines (SW620 and PC3) were 4.24 and 2.78 μM, respectively, followed by the compound 11 h, whose IC₅₀ values against HCT116, LNCaP, SW620, and PC3 cell lines were 2.22, 1.6, 2.37, and 3.21 µM, respectively. The results of apoptosis induction and cell cycle arrest experiments indicate that compounds 11 g and 11 h induced early apoptosis in HCT116 cells, and G2/M phase cell cycle arrest. This finding was further validated through molecular docking analysis and cellular thermal migration and enzyme activity experiments. The results of WRN helicase inhibition assays showed that the IC₅₀ value of compound 11 g was 6.61 µM. In summary, our study identifies 2-amino-4-(trifluoromethyl)pyrimidine derivative 11 g as potential WRN-dependent anticancer agents.

Ureaplasma urealyticum (U. urealyticum) is a sexually transmitted pathogen often causing urogenital tract disorders. The growing challenge of multidrug-resistant strains poses a significant risk for the treatment of U. urealyticum infections. To date, no licensed vaccines are available, and previous attempts to create secure and efficient prophylaxis have been failed. Recent studies have adopted an immunoinformatic strategy based on reverse vaccinology to detect antigenic proteins which are appropriate for the creation of a multi-epitope vaccine. The multi-epitope subunit vaccine, incorporating eleven T-cell and seven B-cell epitopes along with the adjuvant, exhibited strong antigenicity and did not induce allergic responses. Moreover, molecular docking as well as dynamic simulations were utilized to investigate the interaction within the vaccine-adjuvant complex. The prospective effectiveness of the vaccine was verified via immune simulation experiments. Therefore, the vaccine developed in this study represents an effective multi-epitope solution for immunization against U. urealyticum, waiting for further experimental analysis.

IL-17A is a pivotal pro-inflammatory cytokine implicated in a wide spectrum of immunological responses. However, its dysregulation is linked to the progression of various pathological conditions, from mild inflammation to malignant cancers. When IL-17A binds to its cognate receptor, IL-17RA, it forms a complex that initiates a series of molecular signaling cascades within the cell, contributing to various inflammatory processes. Currently, there are no specific oral drugs targeting this pathway, underscoring the urgent need for novel non-inflammatory drugs to address autoimmune and inflammatory diseases. Targeting IL-17A presents a unique opportunity to develop innovative therapies for autoimmune conditions. This research employs ligand-based pharmacophore modeling, followed by screening and docking simulations found six potential drugs that effectively disrupt the IL-17A-IL-17RA combination. Molecular dynamics simulations further demonstrated the stability and inhibitory potential of these compounds, highlighting their interactions within the IL-17A binding site. These interactions involve key residues such as Arg39, Trp51, Trp67, Gln94, Glu95, Leu97, Leu99, Lys114, and Ser118, which are crucial for locking the associated signaling cascade. Mechanistic studies, including dynamic simulations and calculation of free energy, support the efficacy of the identified compounds. Notably, Compounds 1 and 4 exhibit higher binding affinities compared to the native reference inhibitor of target. Our results revealed that both the peptide (Compound 1) and macrocyclic compounds (Compound 3) significantly disrupt the IL-17A/IL-17RA complex, confirming the validity of our approach and reinforcing its potential therapeutic relevance, as highlighted in prior studies. These IL-17A inhibitors show enormous promise as prospective therapeutic candidates for the treatment of inflammatory disorders.