Anti-quorum sensing activity of α-amidoamides against Agrobacterium tumefaciensNT1: Insights from molecular docking and dynamic investigations to synergistic approach of metronidazole release from gel formulations.

A unique approach is imperative for the development of drugs aimed at inhibiting various stages of infection, rather than solely focusing on bacterial viability. Among the array of unconventional targets explored for formulating novel antimicrobial medications, blocking the quorum-sensing (QS) system emerges as a highly effective and promising strategy against a variety of pathogenic microbes. In this investigation, we have successfully assessed nine α-aminoamides for their anti-QS activity using Agrobacterium tumefaciensNT1 as a biosensor strain. Among these compounds, three (2, 3and, 4) have been identified as potential anti-QS candidates. Molecular docking studies have further reinforced these findings, indicating that these compounds exhibit favorable pharmacokinetic profiles. Additionally, we have assessed the ligand's stability within the protein's binding pocket using molecular dynamics (MD) simulations and MMGBSA analysis. Further, combination of antiquorum sensing properties with antibiotics viaself-assembly represents a promising approach to enhance antibacterial efficacy, overcome resistance, and mitigate the virulence of bacterial pathogens. The release study also reflects a slow and gradual release of the metronidazole at both pH 6.5 and pH 7.4, avoiding the peaks and troughs associated with more immediate release formulations.

Zingerone inhibits biofilm formation and enhances antibiotic efficacy against Salmonella biofilm.

Salmonella enterica serovar Typhi is a significant cause of typhoid fever and a major public health problem. The ability of S. Typhi to form biofilms on living and non-living surfaces results in antibiotic resistance and poses a major challenge in health care. In this study, we assessed the ability of zingerone alone and in combination with antibiotics against the motility phenotypes and biofilm-forming ability of S. Typhi. Results showed that zingerone effectively reduced the swimming, swarming, and twitching phenotypes and exhibited biofilm inhibition potential. Moreover, zingerone enhanced the antibiofilm activity of ciprofloxacin and kanamycin. Microscopic analysis revealed a thinner biofilm in the presence of zingerone, which may have enhanced the antibiofilm efficacy of the antibiotics. The microscopic analysis showed that the presence of zingerone resulted in a reduction in the thickness of the biofilm, potentially increasing the antibiofilm efficacy of the antibiotics. In silico molecular docking and simulation studies further indicated that zingerone may bind to the fimbriae subunits (FimA, FimC, FimH, and FimY) of S. Typhi and form stable interactions. These findings provide important insights into the potential of zingerone to target biofilm-associated Salmonella infections. Further research is considered a promising option for designing innovative approaches to prevent infections associated with biofilms. Schematic representation of the role of zingerone in biofilm, motility inhibition and molecular interactions with biofilm associated proteins.

Discovery, lead identification and exploration of potential oxadiazole derivatives in targeting STAT3 as anti-cancer agents.

Oxadiazoles an important heterocyclic scaffold of medicinal importance in the field of drug discovery. In the study, a library of oxadiazole based compounds was selected for screening against STAT-3 as anti-cancer target. STAT3 is a potential target of interest in cancer therapy. A total of 544 screened library of compounds was subjected to molecular docking against STAT-3 (6NJS and 6NQU). The compounds with good dock score and binding interations were further subjected to in-silico ADME analysis followed by toxicity estimation. A total of 141 hits were selected against 6NJS and 50 hits against 6NQU and further screened for kinetic properties and drug likeliness. The compounds were screened on the basis of physico-chemical properties, solubility, gastrointestinal absorption, BBB permeability, synthetic accessibility, Lipinski and other violations. Best compounds obtained after ADME analysis were further subjected for toxicity analysis. Carcinogenecity, mutagenicity, Ames and other important parameters were considered for toxicity based screening. The best leads thus obtained (compound 114 and 40) were further subjected to molecular dynamics against the respective target proteins. MD simulations were run to access the stability of C-114 and C-40 along with the dynamic behaviour of both complexes for about 100 ns and shows good stability with the proteins.

Recent advancement of nanomedicine-based targeted delivery for cervical cancer treatment.

Cervical cancer is a huge worldwide health burden, impacting women in impoverished nations in particular. Traditional therapeutic approaches, such as surgery, radiation therapy, and chemotherapy, frequently result in systemic toxicity and ineffectiveness. Nanomedicine has emerged as a viable strategy for targeted delivery of therapeutic drugs to cancer cells while decreasing off-target effects and increasing treatment success in recent years. Nanomedicine for cervical cancer introduces several novel aspects that distinguish it from previous treatment options such as tailored delivery system, precision targeting, combination therapies, real-time monitoring and diverse nanocarriers to overcome the limitations of one another. This abstract presents recent advances in nanomedicine-based tailored delivery systems for the treatment of cervical cancer. Liposomes, polymeric nanoparticles, dendrimers, and carbon nanotubes have all been intensively studied for their ability to transport chemotherapeutic medicines, nucleic acids, and imaging agents to cervical cancer cells. Because of the way these nanocarriers are designed, they may cross biological barriers and preferentially aggregate at the tumor site, boosting medicine concentration and lowering negative effects on healthy tissues. Surface modification of nanocarriers with targeting ligands like antibodies, peptides, or aptamers improves specificity for cancer cells by identifying overexpressed receptors or antigens on the tumor surface. Furthermore, nanomedicine-based techniques have made it possible to co-deliver numerous therapeutic drugs, allowing for synergistic effects and overcoming drug resistance. In preclinical and clinical investigations, combination treatments comprising chemotherapeutic medicines, gene therapy, immunotherapy, and photodynamic therapy have showed encouraging results, opening up new avenues for individualized and multimodal treatment regimens. Furthermore, the inclusion of contrast agents and imaging probes into nanocarrier systems has enabled real-time monitoring and imaging of treatment response. This enables the assessment of therapy efficacy, the early diagnosis of recurrence, and the optimization of treatment regimens.

Identification and exploration of quinazoline-1,2,3-triazole inhibitors targeting EGFR in lung cancer.

Epidermal growth factor receptor (EGFR) enhances lung cancer development, due to their inability to permeate the cell membrane, secreted growth factors work through specialized signal transduction pathways. The purpose of this study is to find out a novel anticancer agent that inhibits EGFR and reduces the chances of lung cancer. A series of triazole-substituted quinazoline hybrid compounds were designed by Chemdraw software and docked against five different crystallographic EGFR tyrosine kinase domain (TKD). For docking and visualization PyRx, Autodock vina, and Discovery studio visualizer were used. Molecule-14, Molecule-16, Molecule-19, Molecule-20, and Molecule-38 showed significant affinity but Molecule-19 showed excellent binding affinity (-12.4 kcal/mol) with crystallographic EGFR tyrosine kinase. The superimposition of the co-crystalized ligand with the hit compound shows similar conformation at the active site of EGFR (PDB ID: 4HJO) indicating excellent coupling and pharmaceutically active. The hit compound showed a good bioavailability score (0.55) with no sign of carcinogenesis, mutagenesis, or reproductive toxicity properties. MD simulation and MMGBSA represent good stability and binding free energy demonstrating that the hit (Molecule-19) may be used as a lead compound. Molecule-19 also showed good ADME properties, bioavailability scores, and synthetic accessibility with fewer signs of toxicity. It was observed that Molecule-19 may be a novel and potential inhibitor against EGFR with fewer side effects than the reference molecule. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about the amino acid residues involved in binding. Overall, this study led to the identification of potential EGFR inhibitors with favorable pharmacokinetic properties. We believe that the outcome of this study can help to develop more potent drug-like molecules to tackle human lung cancer.

Recent advancement of HDAC inhibitors against breast cancer.

Recent studies highlight the great potential impact of HDAC inhibitors (HDACis) in suppressing TNBC, even though clinical trials including a single HDACis demonstrated unsatisfactory outcomes against TNBC. New compounds created to achieve isoform selectivity and/or a polypharmacological HDAC strategy have also produced interesting results. The current study discusses the HDACis pharmacophoric models and the structural alterations that produced drugs with strong inhibitory effects on TNBC progression. With more than 2 million new cases reported in 2018, breast cancer-the most common cancer among women worldwide-poses a significant financial burden on an already deteriorating public health system. Due to a lack of therapies being developed for triple-negative breast cancers and the development of resistance to the current treatment options, it is imperative to plan novel therapeutics in order to bring new medications to the pipeline. Additionally, HDACs deacetylate a large number of nonhistone cellular substrates that control a variety of biological processes, such as the beginning and development of cancer. The significance of HDACs in cancer and the therapeutic potential of HDAC inhibitor. Furthermore, we also reported molecular docking study with four HDAC inhibitors and performed molecular dynamic stimulation of the best dock score compound. Among the four ligands belinostat compound showed best binding affinity with histone deacetylase protein which was -8.7 kJ/mol. It also formed five conventional hydrogen bond with Gly 841, His 669, His 670, pro 809, and His 709 amino acid residues.