A computer-aided drug design approach to explore novel type II inhibitors of c-Met receptor tyrosine kinase for cancer therapy: QSAR, molecular docking, ADMET and molecular dynamics simulations

Article

作者: Bakhouch, Mohamed ; Nour, Hassan ; Chtita, Samir ; Elkhattabi, Souad ; Abchir, Oussama ; Daoui, Ossama

Small molecules such as 4-phenoxypyridine derivatives have remarkable inhibitory activity against c-Met enzymatic activity and proliferation of cancer cell lines. Since there is a relationship between structure and biological activity of these molecules, these little compounds may have great potential for clinical pharmaceutical use against various types of cancer caused by c-Met activity. The purpose of this study was to remodel the structures of 4-phenoxypyridine derivatives to achieve strong inhibitory activity against c-Met and provide favorable pharmacokinetic properties for drug design and discovery. Therefore, this paper describes the structure-activity relationship and the rationalization of appropriate pharmacophore sites to improve the biological activity of the investigated molecules, based on bioinformatics techniques represented by a computer-aided drug design approach. Accordingly, robust and reliable 3D-QSAR models were developed based on CoMFA and CoMSIA techniques. As a result, 46 lead molecules were designed and their biological and pharmacokinetic activities were predicted in silico. Screening filters by 3D-QSAR, Molecular Docking, drug-like and ADME-Tox identified the computer-designed compounds P54 and P55 as the best candidates to achieve high inhibition of c-Met enzymatic activity compared to the synthesized template compound T14. Finally, through molecular dynamics simulations, the structural properties and dynamics of c-Met free and complex (PDB code: 3LQ8) in the presence of 4-phenoxypyridine-derived compounds in an aqueous environment are discussed. Overall, the rectosynthesis of the designed drug inhibitors (P54 and P55) and their in vitro and in vivo bioactivity evaluation may be attractive for design and discovery of novel drug effective to inhibit c-Met enzymatic activity.Communicated by Ramaswamy H. Sarma.

2006-10-01·Plastic and Reconstructive Surgery

A Novel Perfluoroelastomer Seeded with Adipose-Derived Stem Cells for Soft-Tissue Repair

Article

作者: J Rubin ; Jennifer Bennett ; Vu Nguyen ; Julio Clavijo-Alvarez ; Kacey Marra ; Christopher Underwood ; Jason Dudas

BACKGROUNDThere is a need for engineered soft tissue in reconstructive surgery, particularly after tumor removal. An ideal implant that will provide structural support and a favorable environment for growing cells is a key element in the process of tissue engineering. Nonbiodegradable materials that become well incorporated within the new tissue are a good solution, but many such materials do not have a surface favorable for cell adherence and proliferation. The authors hypothesized that the modification of the pore size in a novel fluoropolymer would improve the adherence and enhance the proliferation of adipose-derived stem cells.METHODSFluoropolymers with two varying pore size ranges were examined. Fluoropolymer compound U48 (pore size, 100 to 180 microm) and fluoropolymer compound P54 (pore size, 10 to 55 microm) were seeded with human adipose-derived stem cells, and cell adherence to the material was measured after 4 hours and cell proliferation was measured after 72 hours. Cell-seeded constructs were implanted subcutaneously in a nude mouse model for 30 days.RESULTSFluoropolymer surface treatment with fibronectin improved the attachment of adipose-derived stem cells to the well plates but did not improve attachment to the fluoropolymer, regardless of pore size. Fluoropolymer U48 increases the adherence and provides a favorable surface for proliferation of adipose-derived stem cells.CONCLUSIONSAfter subcutaneous implantation into nude mice, tissue growth was observed in the fluoropolymer samples with the larger pore size. The characteristics of this new material will allow for future clinical applications in plastic and reconstructive surgery.

2003-04-01·Veterinary Record3区 · 农林科学

Randomised, double‐blind, placebocontrolled parallel group study of P54FP for the treatment of dogs with osteoarthritis

3区 · 农林科学

Article

作者: Burn, J. F. ; Kelly, A. L. ; Innes, J. F. ; Fuller, C. J. ; Grover, E. R.

P54FP is an extract of Indian and Javanese turmeric,Curcuma domesticaandCurcuma xanthorrhizarespectively, which contains a mixture of active ingredients including curcuminoids and essential oils. A randomised, double‐blind, placebo‐controlled, parallel group clinical trial of P54FP as a treatment for osteoarthritis of the canine elbow or hip was conducted to assess its efficacy and safety. Sixty‐one client‐owned dogs with osteoarthritis were recruited through first‐opinion practices and examined at a single centre. After a two‐week wash‐out period, they were randomly allocated to receive P54FP or a placebo orally twice daily for eight weeks, and were re‐examined after four, six and eight weeks of treatment. The effectiveness of the treatment was assessed in terms of the peak vertical force (PVz) and vertical impulse of the affected limbs, as measured with a force platform, by clinical assessments of lameness and joint pain by the investigators, and overall assessments of the response to treatment by the investigators and the owners. The results from 25 P54FP‐treated dogs and 29 placebo‐treated dogs showed that there was no statistically significant difference between the groups in terms of the Pvz of the affected limb. The investigators' overall assessment showed a statistically significant treatment effect in favour of P54FP (P=0.012), but the owners' assessment just failed to reach statistical significance (P=0.063). No serious adverse effects were recorded, but two P54FP‐treated dogs and four placebo‐treated dogs were withdrawn from the study because their condition deteriorated.

100 项与 P-54-FP 相关的药物交易

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