Repurposing celecoxib analogues as leads for antibiotics.

There is an urgent need for new antibiotics and alternative strategies to combat bacterial pathogens. Molecular docking, antibacterial evaluation in vitro and in vivo, cytotoxicity assessment and enzyme inhibition analyses were performed. Compound 12 exhibited antimicrobial activity against Staphylococcus aureus (MIC: 4 µg/ml), various clinically isolated strains of MRSA (MIC: 4-16 µg/ml) and Acinetobacter baumannii (MIC: 4 µg/ml) when combined with subinhibitory concentrations of colistin B. Compound 12 (20 mg/kg) yielded mild improvement in survival of methicillin-resistant Staphylococcus aureus (MRSA)-infected mice. Additionally, enzyme inhibition tests showed that compound 12 exhibited inhibitory effects against S. aureus dihydrofolate reductase (105.1 µg/ml) and DNA gyrase (122.8 µg/ml). Compound 12 is a promising antibacterial candidate for further development.

Rational application of drug promiscuity in medicinal chemistry.

'Drug promiscuity' refers to a drug that can act on multiple molecular targets, exhibiting similar or different pharmacological effects. Drugs may interact with unwanted targets, leading to off-target effects (one of the main reasons for side effects). Thus, intervention to prevent off-target effects in the early stages of drug discovery could reduce the risk of failure. The conversion between target and off-target effects is important for drug repurposing. Drug repurposing strategies could reduce research and development costs. This review details the research progress in the rational application of drug promiscuity for the discovery of multi-target drugs, drug repurposing and improving druggability in medicinal chemistry over the last 5 years.

Design, synthesis and biological evaluation of novel peptide MC62 analogues as potential antihyperglycemic agents.

Two series of peptide MC62 analogues were synthesized, characterized and evaluated for their antihyperglycemic effects. Structure-activity relationship studies of the first series indicated that antihyperglycemic effects were correlated to residues 4, 5, 7 and 8. Peptide I-6 exhibited higher antihyperglycemic activity than the MC62 parent peptide, and was chosen for further modification. Incorporation of Met at position 3 increased potency further and generated II-3, which was screened in vivo and in vitro using exenatide (Ex-4) and GLP-1 as positive controls. The results showed that the antihyperglycemic and antioxidative activities of II-3 were comparable to the positive controls, suggesting II-3 could be a candidate for use as a future diabetic treatment.

Evaluation of hypoglycemic and antioxidative effects of synthesized peptide MC62.

Diabetes mellitus has been considered as a major health problem in the world today. This study aimed to investigate the hypoglycemic and antioxidative effects of peptide MC62 which was synthesized by solid-phase peptide synthesis method against diabetes induced by streptozotocin. MC62 was administered daily and injected intraperitoneally to the diabetic mice at a dose of 1 µmol/kg body weight for 20 days. The levels of fasting blood glucose and HbA1C, pancreatic islet damage, and associated changes in antioxidative activities were evaluated in streptozotocin-induced diabetic mice used the exenatide as positive control. After the administration of MC62 together with exenatide for 20 days, the elevated fasting blood glucose and HbA1C levels were reduced, and antioxidative activities were restored. It was confirmed with the histological finding that MC62 prevented the islet from damage in diabetic mice. This indicated that MC62 can prevent mice from hyperglycemia which may be associated with oxidative stress. It also suggested that MC62 could be used as a safe alternative hypoglycemic candidate for treatment of diabetes.

3D QSAR pharmacophore modeling for c-Met kinase inhibitors.

The receptor tyrosine kinase c-Met has multiple roles during cancer development and is currently considered as a promising target for cancer therapies. Pharmacophore models of c-Met kinase inhibitors have been developed based on 22 diverse compounds by using HypoGen algorithm implemented in Discovery studio program package. The best quantitative pharmacophore model, Hypo 1, which had the highest correlation coefficient (0.9623), consists of two hydrogen bond acceptors, one hydrophobic feature and two excluded volumes. Then best model was validated by test set prediction, Fischer randomization and decoy set. Besides, the features of Hypo1 were verified to correctly reflect the interactions between kinase active site and its ligands by comparison and superimposition of Hypo 1 in active site of c-Met kinase. The results shows that Hypo 1 has strong capability to identify c-Met kinase inhibitors and to predict the activities of structurally diverse molecules. Therefore, our pharmacophore models were considered as valuable tools for the discovery and development of specific c-Met kinase inhibitors.

Structure-activity relationships of a snake cathelicidin-related peptide, BF-15.

Cathelicidin-BF15 (BF-15) is a 15-mer peptide derived from Cathelicidin-BF (BF-30), which is found in the venom of the snake Bungarus fasciatus and exhibits broad antimicrobial activity. Since BF-15 retains most part of the antimicrobial activity of BF-30 but has significantly reduced haemolytic activity and a much shorter sequence length (and less cost), it is a particularly attractive template around which to design novel antimicrobial peptides. However, the structure-activity relationship of it is still unknown. We designed and synthesized a series of C-terminal amidated analogs of BF-15 based on its amphipathic α-helix structure. And we characterized their antimicrobial potency and haemolytic activity. We identified the amidated BF-15 (analog B1) with potent antimicrobial activity against several antibiotic-resistant bacteria (MICs between 1 and 64 µg/mL, 2-16-folds higher than BF-30) and much lower haemolytic activity. The subsequent circular dichroism study results showed a typical α-helix pattern of analog B1 and the content of the α-helix structure of it increased significantly comparing with BF-30, which indicates the peptide sequence of BF-15 may provide a major contribution to the α-helix content of the whole BF-30 sequence. The peptide induced chaotic membrane morphology and cell debris as determined by electron microscopy. This suggests that the antimicrobial activity of B1 is based on cytoplasmic membrane permeability. Taken together, our results suggested that peptide B1 should be considered as an excellent candidate for developing therapeutic drugs.