Read by QxMD icon Read

New drug discovery

Sean Ekins, Alexander L Perryman, Carolina Horta Andrade
The Zika virus outbreak in the Americas has caused global concern. To help accelerate this fight against Zika, we launched the OpenZika project. OpenZika is an IBM World Community Grid Project that uses distributed computing on millions of computers and Android devices to run docking experiments, in order to dock tens of millions of drug-like compounds against crystal structures and homology models of Zika proteins (and other related flavivirus targets). This will enable the identification of new candidates that can then be tested in vitro, to advance the discovery and development of new antiviral drugs against the Zika virus...
October 2016: PLoS Neglected Tropical Diseases
Nicole Robbins, Gerard D Wright, Leah E Cowen
Invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. The fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus collectively contribute to over 1 million human deaths annually. Hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for drug development remains limited...
October 2016: Microbiology Spectrum
Madhukar Pai, Mark P Nicol, Catharina C Boehme
Rapid and accurate diagnosis is critical for timely initiation of anti-tuberculosis (TB) treatment, but many people with TB (or TB symptoms) do not have access to adequate initial diagnosis. In many countries, TB diagnosis is still reliant on sputum microscopy, a test with known limitations. However, new diagnostics are starting to change the landscape. Stimulated, in part, by the success and rollout of Xpert MTB/RIF, an automated, molecular test, there is now considerable interest in new technologies. The landscape looks promising with a pipeline of new tools, particularly molecular diagnostics, and well over 50 companies actively engaged in product development, and many tests have been reviewed by WHO for policy endorsement...
October 2016: Microbiology Spectrum
V R Knight-Schrijver, V Chelliah, L Cucurull-Sanchez, N Le Novère
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response...
2016: Computational and Structural Biotechnology Journal
András Füredi, Szilárd Tóth, Kornélia Szebényi, Veronika F S Pape, Dóra Türk, Nóra Kucsma, László Cervenák, József Tóvári, Gergely Szakács
Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study our aim was to catalogue various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp) overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp...
October 19, 2016: Molecular Cancer Therapeutics
Eugen Widmeier, Weizhen Tan, Merlin Airik, Friedhelm Hildebrandt
INTRODUCTION: Steroid-resistant nephrotic syndrome (SRNS) inevitably progresses to end-stage kidney disease, requiring dialysis or transplantation for survival. However, treatment modalities and drug discovery remain limited. Mutations in over 30 genes have been discovered as monogenic causes of SRNS. Most of these genes are predominantly expressed in the glomerular epithelial cell, the podocyte, placing it at the center of the pathogenesis of SRNS. Podocyte migration rate (PMR) represents a relevant intermediate phenotype of disease in monogenic causes of SRNS...
October 19, 2016: American Journal of Physiology. Renal Physiology
Scott J Hughes, Leanne Barnard, Katayoun Mottaghi, Wolfram Tempel, Tetyana Antoshchenko, Bum Soo Hong, Abdellah Allali-Hassani, David Smil, Masoud Vedadi, Erick Strauss, Hee-Won Park
The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanKII with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm...
September 9, 2016: ACS Infectious Diseases
Maria Rosaria Carratù, Anna Signorile, Domenico De Rasmo, Antonia Reale, Angelo Vacca
BACKGROUND: The serine-threonine protein phosphatase 2A (PP2A) regulates multiple cell signaling cascades and its inactivation by viral oncoproteins, mutation of specific structural subunits or upregulation of the cellular endogenous inhibitors may contribute to malignant transformation by regulating specific phosphorylation events. Pharmacological modulation of PP2A activity is becoming an attractive strategy for cancer treatment. Some compounds targeting PP2A are able to induce PP2A reactivation and subsequent cell death in several types of cancer...
October 14, 2016: Current Medicinal Chemistry
Vibhuti Joshi, Ayeman Amanullah, Arun Upadhyay, Ribhav Mishra, Amit Kumar, Amit Mishra
Cells regularly synthesize new proteins to replace old and abnormal proteins for normal cellular functions. Two significant protein quality control pathways inside the cellular milieu are ubiquitin proteasome system (UPS) and autophagy. Autophagy is known for bulk clearance of cytoplasmic aggregated proteins, whereas the specificity of protein degradation by UPS comes from E3 ubiquitin ligases. Few E3 ubiquitin ligases, like C-terminus of Hsc70-interacting protein (CHIP) not only take part in protein quality control pathways, but also plays a key regulatory role in other cellular processes like signaling, development, DNA damage repair, immunity and aging...
2016: Frontiers in Molecular Neuroscience
Mohammad A Ghattas, Noor Raslan, Asil Sadeq, Mohammad Al Sorkhy, Noor Atatreh
Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability...
2016: Drug Design, Development and Therapy
Kenji Ueda, Teruhiko Beppu
Today, the frequency of discovery of new antibiotics in microbial culture is significantly decreasing. The evidence from whole-genome surveys suggests that many genes involved in the synthesis of unknown metabolites do exist but are not expressed under conventional cultivation conditions. Therefore, it is urgently necessary to study the conditions that make otherwise silent genes active in microbes. Here we overview the knowledge on the antibiotic production promoted by cocultivation of multiple microbial strains...
October 19, 2016: Journal of Antibiotics
Mark D Mathew, Neal D Mathew, Angela Miller, Mike Simpson, Vinci Au, Stephanie Garland, Marie Gestin, Mark L Edgley, Stephane Flibotte, Aruna Balgi, Jennifer Chiang, Guri Giaever, Pamela Dean, Audrey Tung, Michel Roberge, Calvin Roskelley, Tom Forge, Corey Nislow, Donald Moerman
BACKGROUND: The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes...
October 2016: PLoS Neglected Tropical Diseases
Anna Dominiczak
Human primary or essential hypertension is a complex, polygenic trait with some 50% contribution from genes and environment. Richard Lifton and colleagues provided elegant dissection of several rare Mendelian forms of hypertension, exemplified by the glucocorticoid remediable aldosteronism and Liddle's syndrome. These discoveries illustrate that a single gene mutation can explain the entire pathogenesis of severe, early onset hypertension as well as dictating the best treatment.The dissection of the much more common polygenic hypertension has proven much more difficult...
September 2016: Journal of Hypertension
Dennis G Hall, Taras Rybak, Tristan Verdelet
Multicomponent reactions (MCR), transformations employing three or more simple substrates in a single and highly atom-economical operation, are very attractive in both natural product synthesis and diversity-oriented synthesis of druglike molecules. Several popular multicomponent reactions were designed by combining two well-established individual reactions that utilize mutually compatible substrates. In this regard, it is not surprising that the merging of two reactions deemed as workhorses of stereoselective synthesis, the Diels-Alder cycloaddition and carbonyl allylboration, would produce a powerful and highly versatile tandem MCR process...
October 18, 2016: Accounts of Chemical Research
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Angel R de Lera, A Ganesan
The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders...
2016: Clinical Epigenetics
Muhammad Irfan, Sumeira Rabel, Quratulain Bukhtar, Muhammad Imran Qadir, Farhat Jabeen, Ahmed Khan
Over the past few decades, tendency toward innovative drug delivery systems has majorly increased attempts to ensure efficacy, safety and patient acceptability. As discovery and development of new chemical agents is a complex, expensive and time consuming process, so recent trends are shifting toward designing and developing innovative drug delivery systems for existing drugs. Out of those, drug delivery system being very eminent among pediatrics and geriatrics is orally disintegrating films (ODFs). These fast disintegrating films have superiority over fast disintegrating tablets as the latter are associated with the risks of choking and friability...
September 2016: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Mélanie V Trudel, Antony T Vincent, Sabrina A Attéré, Myriam Labbé, Nicolas Derome, Alexander I Culley, Steve J Charette
The bacterium Aeromonas salmonicida subsp. salmonicida is a common pathogen in fish farms worldwide. Since the antibiotic resistance of this bacterial species is on the increase, it is important to have a broader view on this issue. In the present study, we tested the presence of known plasmids conferring multi-drug resistance as well as antibiotic resistance genes by a PCR approach in 100 Canadian A. salmonicida subsp. salmonicida isolates. Our study highlighted the dominance of the conjugative pSN254b plasmid, which confers multi-drug resistance...
October 18, 2016: Scientific Reports
Yehoshua Perl, James Geller, Michael Halper, Christopher Ochs, Ling Zheng, Joan Kapusnik-Uner
The purpose of the Big Data to Knowledge initiative is to develop methods for discovering new knowledge from large amounts of data. However, if the resulting knowledge is so large that it resists comprehension, referred to here as Big Knowledge (BK), how can it be used properly and creatively? We call this secondary challenge, Big Knowledge to Use. Without a high-level mental representation of the kinds of knowledge in a BK knowledgebase, effective or innovative use of the knowledge may be limited. We describe summarization and visualization techniques that capture the big picture of a BK knowledgebase, possibly created from Big Data...
October 17, 2016: Annals of the New York Academy of Sciences
Fatiha Benmansour, Iuni Trist, Bruno Coutard, Etienne Decroly, Gilles Querat, Andrea Brancale, Karine Barral
With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase...
October 5, 2016: European Journal of Medicinal Chemistry
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"