Molecular Diversity最新文献

Designing peptide binders is a widely used strategy for developing potential therapeutic agents. Fibroblast Growth Factor 7 (FGF7) plays a critical role in cell proliferation and tissue repair, and its dysregulation is associated with various diseases. Here, we established an integrated computational-experimental workflow to identify peptide inhibitors targeting FGF7. We first generated a library of 100,000 random 8-mer peptides and progressively narrowed it using peptide toxicity analysis and binder prediction via PepBind-SVM. These methods eliminated 75.8% of non-viable candidates, enabling rapid library refinement. Next, we applied a sequence-based machine learning approach incorporating principal component analysis to classify the remaining peptides. The random candidates from three identical cluster were selected and subjected to molecular docking using Rosetta FlexPepDock. Peptides with the highest predicted binding affinity were synthesized and experimentally validated using isothermal titration calorimetry (ITC). Eight peptides demonstrated measurable binding to recombinant human FGF7 (rhFGF7), with three peptides exhibiting notably higher affinities of 43-67 µM. While these affinities are relatively weak and may limit immediate biological relevance, they nevertheless confirm binding and highlight both the potential and current limitations of the pipeline. Further molecular dynamics simulations revealed that key FGF7 residues, including R65, R67, and N149 play significant roles in stabilizing peptide interactions. This study presents an integrated in silico-to-in vitro pipeline for identifying preliminary peptide binders of FGF7 and provides mechanistic insights that may inform subsequent optimization and rational peptide design.

The coexistence of altered or overexpressed penicillin-binding protein 3 (PBP3) and β-lactamases has led to a significant decrease in treatment success rates of Klebsiella pneumoniae. Targeting both proteins simultaneously could offer a robust strategy to overcome resistance in K. pneumoniae. Herein, a curated library of 147,953 terpenoids-renowned for their structural diversity and multi-targeting potential against bacterial pathways-was screened via structure-based pharmacophore modelling and molecular docking. Five terpenoids with higher binding tendencies for K. pneumoniae PBP3 and KPC-2 beta-lactamase were identified. These leads exhibited favourable pharmacokinetic, drug-likeness, and low toxicity profiles. The most promising leads (TP93780 and TP156670) demonstrated superior binding free energies (BFE) against K. pneumoniae PBP3 (- 24.40 ± 5.20 and - 23.46 ± 3.50 kcal/mol) and KPC-2 beta-lactamase (- 15.38 ± 4.09 and - 16.83 ± 3.75 kcal/mol) when compared to ceftaroline (- 21.82 ± 8.64 kcal/mol) and clavulanate (- 10.85 ± 34.40 kcal/mol), respectively. The energetics revealed that the promising leads were driven by balanced hydrophobic and moderate electrostatic interactions, compared to the polar-dominated binding profile of the reference standards. The post-molecular dynamics structural analysis revealed an enhanced overall stability of the TP93780 and TP156670 bound structures. The principal component analysis and free energy landscape analyses revealed more constrained and localised motions in the bound structures compared to the unbound structures and reference standard bound complexes. The favourable molecular orbital energies and the thermodynamically stable terpenoid-bound structures underpin their potential as dual modulators of K. pneumoniae PBP3 and KPC-2 beta-lactamase. Further in vitro studies are underway.

The re-emergence of monkeypox virus (MPXV), renamed mpox, as a global health emergency in 2022 has intensified the search for robust therapeutic interventions. This review summarizes the virological, structural, and pharmacological dimensions of MPXV, with a focus on the virus's lifecycle from host cell entry to dissemination. MPXV's double-stranded DNA genome exhibits clade-specific plasticity, with variations in genes like OPG065 and MOPICE driving virulence, immune evasion, and host adaptation. Key viral proteins, including entry facilitators A27L and L1R, envelope protein F13L (VP37), and immune modulators such as B19R and C12L, serve as critical targets for antiviral strategies. Structural insights from cryo-EM and X-ray crystallography reveal conserved motifs across orthopoxviruses, enabling pan-orthopox drug design. Current therapeutics, such as tecovirimat (targeting VP37 to block egress), brincidofovir, and cidofovir (inhibiting DNA polymerase E9L), offer symptomatic relief but face hurdles like resistance mutations (e.g., A314V in E9L) and suboptimal efficacy in immunocompromised patients. Emerging resistance underscores the need for vigilant genomic surveillance. Novel modalities, including monoclonal antibodies against antigenic proteins like A35R and M1R, cytokine-based immunotherapies, and host-directed agents modulating autophagy or interferon pathways, show promise. Computational approaches integrating AI-driven screening, molecular dynamics simulations, and multi-omics have pinpointed repurposed candidates like lumacaftor and conivaptan as VP37 inhibitors. This integrative framework advocates for combination therapies, personalized regimens based on clade profiling, and global collaboration to mitigate MPXV's adaptive potential. By bridging virology and pharmacology, the review charts pathways for innovative drug development to combat this zoonotic threat effectively.

Nitrogen-containing heterocycles owing to their unique physicochemical properties and biological effects are always of paramount importance for the development of novel class of bioactive molecules or potential lead molecules. Nitrogen containing heterocycles have tremendous potential to be developed as bioactive molecules which could inspired medicinal chemists to devise novel and greener methodologies to access them. Quinoxaline is one such valuable and indispensable scaffold having plethora of biological activities. The chemical structure of quinoxaline comprises a fused benzene and pyrazine ring. The broad spectrum of pharmacological activities of quinoxaline includes "anticancer", "antimicrobial", "antitubercular", "antiviral", "antileprotic" and "hepatoprotective". The current review, encompasses the contemporary advancements in the role of kinase and various quinoxaline based small molecule kinase inhibitors reported between 2009 and 2024 with special emphasis on their emerging mechanisms of action. The current manuscript highlights some of the recent seminal literature reports pertaining to the structural modifications carried out on quinoxaline scaffold to develop a novel anticancer agent having kinase inhibitory activity.

A direct C-H imidoylmethylation and subsequent oxidation/cyclization reaction of 2-arylbenzimidazoles with CF₃-imidoyl sulfoxonium ylides via Rh(III)/Cu(II) relay catalysis has been developed. This reaction proceeded under mild conditions in an O₂ atmosphere to afford an array of CF₃-decorated imidazo[2,1-a]isoquinolin-5-ones, where O₂ acts as the oxygen donor for carbonyl group formation. This transformation involved an unprecedented cascade process including Rh(III)-catalyzed C-H imidoylmethylation and Cu(II)-mediated oxidation followed by cyclization. Notably, antitumor activity study revealed that some synthetic products exhibit promising antiproliferative activity against several cancer cell lines.

Guanosine monophosphate synthetase (GMPS) catalyzes the ATP-dependent conversion of xanthosine monophosphate (XMP) to guanosine monophosphate (GMP), a key step in de novo purine biosynthesis. Dysregulation of GMPS expression has been implicated in multiple cancers, underscoring its potential as a therapeutic target. Here, we identified a novel small molecule GMPS inhibitor, G18, through large-scale virtual screening of 1.27 million compounds. Biochemical validation using an inorganic phosphatase (IPP1)-coupled colorimetric assay demonstrated that G18 inhibits GMPS with an IC₅₀ of 73.8 μM. Isothermal titration calorimetry (ITC) confirmed direct and thermodynamically favorable binding (Kd = 6.94 μM). Moreover, G18 suppressed HeLa cell proliferation with an IC₅₀ of 73.3 μM. Structural modeling and 500-ns molecular dynamics simulations revealed that G18 binds within the ATPase domain, forming stable hydrogen-bonding and hydrophobic interactions that stabilize the enzyme-inhibitor complex. Together, these results identify G18 as a promising lead compound for GMPS-targeted anticancer drug discovery and provide structural insights for further optimization.

The abnormal function of histone lysine demethylase 6B (KDM6B) is closely associated with the development and progression of various human diseases, including cancer, inflammatory disorders, and psychiatric conditions, supporting KDM6B as a significant therapeutic target. However, the development of potent and selective KDM6B inhibitors remains a critical unmet need. Based on the hit compound (A01) discovered by enzyme-level screening, a series of derivatives with quinazoline scaffold were designed, synthesized and identified as KDM6B inhibitors. Among these, compound 13k exhibited optimal potency (IC₅₀ = 1.8 μM) with superior selectivity over other JMJD subfamily members. Furthermore, 13k upregulates histone methylation levels in THP-1 cells, highlighting its functional effect in a cellular context. This study provides a promising scaffold for developing selective KDM6B inhibitors, as well as delivers a tool compound for probing the biological functions of KDM6B. These findings offer a potential lead for future KDM6B-targeted drug discovery.

Quinazoline, a nitrogen-containing heterocyclic compound, is widely recognized as a "privileged structure" in the process of drug development. Quinazoline and its derivatives are benzene-pyrimidine fusion compounds that exhibit a broad spectrum of pharmacological properties, including anticarcinogenic, anticonvulsive, and antimicrobial characteristics. Quinazoline-2,4(1H,3H)-dione, an oxidized quinazoline derivative (at positions 2 and 4), possesses a diverse range of pharmacological applications. Quinazoline-2,4(1H,3H)-dione is frequently utilized as a scaffold for synthesizing novel compounds, and recent studies have highlighted its potential in oncotherapy. The derivatives of this compound have been investigated in various types of cancer, such as glioblastoma, osteosarcoma, fibrosarcoma, melanoma, colorectal, prostate, breast, and ovarian cancers. These derivatives have been shown to inhibit critical pathways, such as the Wnt signalling pathway in cancer cells. This review emphasizes the role of quinazoline-2,4(1H,3H)-dione as a versatile scaffold in medicinal chemistry and provides a systematic discussion of its derivatives with a special focus on oncology. We have analyzed structure-activity relationships (SAR), identifying the most promising substitutions at N1, N3, and specific positions on the benzene ring that enhance activity and selectivity. Furthermore, the dual-target inhibition displayed by some derivatives suggests their potential for multi-targeting ability. However, detailed investigations into their broader impact on cancer-related signalling pathways are still limited. The derivatives have also exhibited notable antimicrobial, anticonvulsant, antiinflammatory, antioxidant, antihypertensive, antimalarial, antileishmanial and antidiabetic properties. This study further emphasizes the significance of the quinazoline-2,4(1H,3H)-dione scaffold in drug development.