Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

BACKGROUND: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. METHODOLOGY/PRINCIPAL FINDINGS: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. CONCLUSIONS/SIGNIFICANCE: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request

Natural products in drug discovery: advances and opportunities

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities

Polyyne Hybrid Compounds from Notopterygium incisum with Peroxisome Proliferator-Activated Receptor Gamma Agonistic Effects

[Image: see text] In the search for peroxisome proliferator-activated receptor gamma (PPARγ) active constituents from the roots and rhizomes of Notopterygium incisum, 11 new polyacetylene derivatives (1–11) were isolated. Their structures were elucidated by NMR and HRESIMS as new polyyne hybrid molecules of falcarindiol with sesquiterpenoid or phenylpropanoid moieties, named notoethers A–H (1–8) and notoincisols A–C (9–11), respectively. Notoincisol B (10) and notoincisol C (11) represent two new carbon skeletons. When tested for PPARγ activation in a luciferase reporter assay with HEK-293 cells, notoethers A–C (1–3), notoincisol A (9), and notoincisol B (10) showed promising agonistic activity (EC(50) values of 1.7 to 2.3 μM). In addition, notoincisol A (9) exhibited inhibitory activity on NO production of stimulated RAW 264.7 macrophages

A virtual screening approach for identifying plants with anti H5N1 neuraminidase activity

Recent outbreaks of highly pathogenic and occasional drug-resistant influenza strains have highlighted the need to develop novel anti-influenza therapeutics. Here, we report computational and experimental efforts to identify influenza neuraminidase inhibitors from among the 3000 natural compounds in the Malaysian-Plants Natural-Product (NADI) database. These 3000 compounds were first docked into the neuraminidase active site. The five plants with the largest number of top predicted ligands were selected for experimental evaluation. Twelve specific compounds isolated from these five plants were shown to inhibit neuraminidase, including two compounds with IC50 values less than 92 μM. Furthermore, four of the 12 isolated compounds had also been identified in the top 100 compounds from the virtual screen. Together, these results suggest an effective new approach for identifying bioactive plant species that will further the identification of new pharmacologically active compounds from diverse natural-product resources

Lessons learnt by IRSN about the involvement of experts towards the population in contaminated areas in Fukushima Prefecture

International audienceSince November 2011, Institut de radioprotection et de sûreté nucléaire (IRSN) experts have participated in the International Commission on Radiological Protection’s (ICRP) dialogue initiative for the rehabilitation of living conditions after the Fukushima accident. In 2013, IRSN and Centre d’étude sur l’Evaluation de la Protection dans le domaine Nucléaire (CEPN) launched a study to identify the main lessons that can be learned from these dialogues, and benefit French IRSN experts in the event of a postaccident situation. The main lesson is that in order to protect the inhabitants of contaminated areas efficiently, experts must work in cooperation with local actors to develop a co-expertise process. The availability of measurement devices for inhabitants is crucial to allow them to assess their own radiological situation. Measuring radioactivity makes it visible, and allows individuals to discuss the results in their communities and develop local projects to improve their daily life. Eventually, inhabitants create a practical radiological protection culture to manage their situation. However, helping people to protect themselves does not mean that authorities and experts have no responsibilities, and this calls for strong ethical principles such as not making decisions for people about their future. To be helpful, scientists need to understand that, as necessary as radiation protection is, it is not the only problem that inhabitants are facing and it cannot control people's lives. Radiation protection experts must commit themselves to be at the service of individuals and the community, and the issues they want to address. © 2017, © The International Society for Prosthetics and Orthotics

The role of experts in postaccident recovery lessons learnt from Chernobyl and Fukushima

International audienceFollowing a nuclear accident, a major dilemma for affected people is whether to stay or leave the affected area, or, for those who have been evacuated, whether or not to return to the decontaminated zones. Populations who have to make such decisions have to consider many parameters, one of which is the radiological situation. Feedback from Chernobyl and Fukushima has demonstrated that involvement and empowerment of the affected population is a way to provide them with the necessary elements to make informed decisions and, if they decide to return to decontaminated areas, to minimise exposure by contributing to the development of a prudent attitude and vigilance towards exposure. However, involving stakeholders in postaccident management raises the question of the role of experts and public authorities in supporting the inhabitants who have to make decisions about their future. Based on experiences in Chernobyl and Fukushima, this paper will discuss various principles that have to be taken into account by experts and public authorities about their role and position when dealing with stakeholders in a postaccident recovery process. © 2018, The International Society for Prosthetics and Orthotics