ABSTRACT
Preoperative assessment typically equates to evaluating and accepting the presenting condition of the patient (unless extreme) and commonly occurs only a few days before the planned surgery. While this timing enables a preoperative history and examination and mitigates unexpected findings on the day of surgery that may delay throughput, it does not allow for meaningful preoperative management of modifiable medical conditions. Evidence is limited regarding how best to balance efforts to mitigate modifiable risk factors versus the timing of surgery. Furthermore, while the concept of preoperative risk modification is not novel, evidence is lacking for successful and sustained implementation of such an interdisciplinary, collaborative program. A better understanding of perioperative care coordination and, specifically, implementing a preoperative preparation process can enhance the value of surgery and surgical population health. In this article, we describe the implementation of a collaborative preoperative clinic with the primary goal of improving patient outcomes.
Subject(s)
Preoperative Care/methods , Risk Assessment , Ambulatory Surgical Procedures , Delivery of Health Care, Integrated , Documentation , Elective Surgical Procedures , Humans , Patient Care Team , Perioperative Care , Postoperative Complications/prevention & control , Preoperative Care/standards , Risk Factors , Treatment OutcomeABSTRACT
The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(™) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(™)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.
Subject(s)
Drug Discovery/methods , Mitogen-Activated Protein Kinase 14/chemistry , Small Molecule Libraries/chemistry , Triazoles/chemistry , Binding Sites , Bridged Bicyclo Compounds/chemistry , Drug Evaluation, Preclinical/methods , Humans , Ligands , Molecular Conformation , Peptide Fragments/chemistry , Protein Binding , Surface Plasmon Resonance/methods , X-Ray DiffractionABSTRACT
The study of protein target families, as opposed to single targets, has become a very powerful tool in chemogenomics-led drug discovery. By integrating comprehensive chemoinformatics and bioinformatics databases with customised analytical tools, a 'Toolkit' approach for the target family is possible, thus allowing predictions of the ligand class, affinity, selectivity and likely off-target issues to be made for the guidance of the medicinal chemist. In this review, we highlight the development and application of the Toolkit approach to the protein kinase superfamily, drawing on examples from lead optimisation studies and the design of focused libraries for lead discovery.
Subject(s)
Drug Design , Genomics , Protein Kinases/metabolism , Amino Acid Sequence , Molecular Sequence Data , Protein Kinases/chemistry , Sequence Homology, Amino AcidABSTRACT
The metabolic stability of benzoxazinone derivatives, a potent series of NPY Y5 antagonists, has been investigated. This study resulted in the identification of the structural moieties prone to metabolic transformations and which strongly influenced the in vitro half-life. This provides opportunities to optimize the structure of this new class of NPY Y5 antagonists.
