Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful

Calendar of Meetings, (National, State, Examining Boards) / Montana State Dental Society / New Mexico State Dental Society / Delaware Board of Dental Examiners / The American Dental Society of Europe / Massachusetts State Dental Hygienists' Association / Xi Psi Phi Alumni / The Health Exhibit / Association of Dental Examiners, United States Veteran's Bureau/ Trowel Fraternity / Psi Omega Fraternity / An Invitation from the Portland District Dental Society / Dental Corps Orders from War Department / Transportation Arrangements for Los Angeles Meeting

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Facing the challenge of polypharmacy when prescribing for older people with cardiovascular disease. A review by the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy

Population ageing has resulted in an increasing number of older people living with chronic diseases (multimorbidity) requiring five or more medications daily (polypharmacy). Ageing produces important changes in the cardiovascular system and represents the most potent single cardiovascular risk factor. Cardiovascular diseases (CVDs) constitute the greatest burden for older people, their caregivers, and healthcare systems. Cardiovascular pharmacotherapy in older people is complex because age-related changes in body composition, organ function, homeostatic mechanisms, and comorbidities modify the pharmacokinetic and pharmacodynamic properties of many commonly used cardiovascular and non-cardiovascular drugs. Additionally, polypharmacy increases the risk of adverse drug reactions and drug interactions, which in turn can lead to increased morbi-mortality and healthcare costs. Unfortunately, evidence of drug efficacy and safety in older people with multimorbidity and polypharmacy is limited because these individuals are frequently underrepresented/excluded from clinical trials. Moreover, clinical guidelines are largely written with a single-disease focus and only occasionally address the issue of coordination of care, when and how to discontinue treatments, if required, or how to prioritize recommendations for patients with multimorbidity and polypharmacy. This review analyses the main challenges confronting healthcare professionals when prescribing in older people with CVD, multimorbidity, and polypharmacy. Our goal is to provide information that can contribute to improving drug prescribing, efficacy, and safety, as well as drug adherence and clinical outcomes