Search results for "Drug Design"
showing 10 items of 232 documents
Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors
2021
Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues. Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its …
Development of trackable metal-based drugs: new generation of therapeutic agents
2016
International audience; In medicinal chemistry, the aim is not only to conceive ever more efficient molecules, but also to understand their mechanism of action. In very recent years, a new promising strategy was developed to tackle this issue: the conception of trackable therapeutic agents. Metal-based drugs are ideal to exploit this expanding area of research.
Synthesis and comparison of the antiinflammatory activity of manoalide and cacospongionolide B analogues.
1998
We have synthesized analogues of two naturally occurring antiinflammatory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. The two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was considered essential to irreversibly inactivate phospholipase A 2 (PLA 2 ). The two series of compounds were tested for their inhibitory effects on secretory PLA 2 belonging to the groups I, II, and III, and the activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In addi…
Pharmacological distribution diagrams: a tool for de novo drug design.
1996
Abstract Discriminant analysis applied to SAR studies using topological descriptors allows us to plot frequency distribution diagrams: a function of the number of drugs within an interval of values of discriminant function vs. these values. We make use of these representations, pharmacological distribution diagrams (PDDs), in structurally heterogeneous groups where generally they adopt skewed Gaussian shapes or present several maxima. The maxima afford intervals of discrimianant function in which exists a good expectancy to find new active drugs. A set of β-blockers with contrasted activity has been selected to test the ability of PDDs as a visualizing technique, for the identification of n…
RATIONAL DESIGN AND SYNTHESIS OF NOVEL INHIBITORS OF EPIGENETIC TARGET INVOLVED IN CANCER
2021
Protocol for rational design of covalently interacting inhibitors.
2014
The inhibition potencies of covalent inhibitors mainly result from the formation of a covalent bond to the enzyme during the inhibition mechanism. This class of inhibitors has essentially been ignored in previous target-directed drug discovery projects because of concerns about possible side effects. However, their advantages, such as higher binding energies and longer drug-target residence times moved them into the focus of recent investigations. While the rational design of non-covalent inhibitors became standard the corresponding design of covalent inhibitors is still in its early stages. Potent covalent inhibitors can be retrieved from large compound libraries by covalent docking approa…
A high-quality homology model for the human dopamine transporter validated for drug design purposes.
2018
The human dopamine transporter (hDAT) plays many vital functions within the central nervous system and is thus targeted by many pharmaceutical agents. Dopamine-related therapies are in current development for individuals with dopamine-related disorders including depression, Parkinson's disease, and psychostimulant addictions such as cocaine abuse. Yet, most efforts to develop new dopamine therapies are within costly structure-activity relationship studies. Through structure-based drug design techniques, the binding site of hDAT can be utilized to develop novel selective and potent dopamine therapies at reduced costs. However, no structural models of hDAT specifically validated for rational …
Immunotoxicity of Therapeutic Antibodies and Nanoparticles.
2020
Therapeutic antibodies and nanotherapeutic drugs are of great concern due to their widespread use against numerous diseases worldwide. They are frequently used for targeted therapy under the assumption that they cause fewer side effects than nontargeted drugs. Despite their specificity and particular design for therapeutic actions, they might still exhibit unintended adverse effects in the immune system. Immunotoxicity reactions are mediated by immunomodulation, including immunostimulation and immunosuppression. The present review gives an overview on the adverse immunotoxic effects induced by therapeutic antibodies as well as nanotherapeutic drugs. In this context, future methods combining…
Modeling caspase-1 inhibition: Implications for catalytic mechanism and drug design.
2019
Abstract The metabolic product of caspase-1, IL-1β, is an important mediator in inflammation and pyroptosis cell death process. Alzheimer's disease, septic shock and rheumatoid arthritis are IL-1β mediated diseases, making the caspase-1 an interesting target of pharmacological value. Many inhibitors have been developed until now, most of them are peptidomimetic with improved potency. In the present study, all-atom molecular dynamics simulations and the MM/GBSA method were employed to reproduce and interpret the results obtained by in vitro experiments for a series of inhibitors. The analysis shows that the tautomeric state of the catalytic His237 impact significantly the performance of the …
X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors.
2015
1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase inhibitors (CAIs). During X-ray crystallographic experiments an unexpected hydrolysis of the isothiazole ring was evidenced which allowed us to prepare highly potent enzyme inhibitors with selectivity for some isoforms with medical applications.