Hunt For Drugs Research Articles

Identification of DDX5 as a Potential Therapeutic Target of Osteosarcoma Using Thiazolone Probes.

Osteosarcoma (OS) is a rare malignant tumor that has predominantly affected children and adolescents in the past 50 years. The genomes of OS tumors exhibit a high degree of complexity, which leads to the great challenge of target identification for anti-OS. To date, no efficient therapeutic target for the treatment of OS has been validated in clinical practice. In our previous drug hunting for the treatment of OS by phenotypic screening, we found that thiazolone derivate (R)-8i was an effective and selective inhibitor against OS in MNNG/HOS cells and in vivo. However, the mechanism of action and specific molecular targets of (R)-8i remain unclear. In this study, we design and synthesize the photo-cross-linking probes based on the lead compound (R)-8i and identify DDX5 as a potential target protein using an activity-based protein profiling strategy. Further experiments including Western blot, shRNA knockdown experiments, cell colony formation, wound healing assays, and cellular thermal shift assays support that (R)-8i binds to DDX5 and induces its degradation, which affect cell proliferation and migration through the PI3K-AKT-mTOR signaling pathway. The research shows that DDX5 is a potential therapeutic target for the treatment of OS.

Network-base approaches to identify therapeutic biomarkers in hepatocellular carcinoma and search for drug hunting utilizing molecular dynamics simulations

The presence of conditions like Alpha-1 antitrypsin deficiency, hemochromatosis, non-alcoholic fatty liver diseases and metabolic syndrome can elevate the susceptibility to hepatic cellular carcinoma (HCC). Utilizing network-based gene expression profiling via network analyst tools, presents a novel approach for drug target discovery. The significance level (p-score) obtained through Cytoscape in the intended center gene survival assessment confirms the identification of all target center genes, which play a fundamental role in disease formation and progression in HCC. A total of 1064 deferential expression genes were found. These include MCM2 with the highest degree, followed by 4917 MCM6 and MCM4 with a 3944-degree score. We investigated the regulatory kinases involved in establishing the protein-protein interactions network using X2K web tool. The docking approach yields a favorable binding affinity of −8.7 kcal/mol against the target MCM2 using Auto-Dock Vina. Interestingly after simulating the complex system via AMBER16 package, results showed that the root mean square deviation values remained within 4.74 Å for a protein and remains stable throughout the time intervals. Additionally, the ligand’s fit to the protein exhibited fluctuations at some intervals but remains stable. Finally, Gibbs free energy was found to be at its lowest at 1 kcal/mol which presents the real time interactive binding of the atomic residues among inhibitor and protein. The displacement of the ligand was measured showing stable movement and displacement along the active site. These findings increased our understanding for potential biomarkers in hepatocellular carcinoma and an experimental approach will further enhance our outcomes in future. Communicated by Ramaswamy H. Sarma

Physical exercise in amyotrophic lateral sclerosis: a potential co-adjuvant therapeutic option to counteract disease progression.

Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the selective degeneration of upper and lower motor neurons, leading to progressive muscle weakness and atrophy. The mean survival time is two to fiveyears. Although the hunt for drugs has greatly advanced over the past decade, no cure is available for ALS yet. The role of intense physical activity in the etiology of ALS has been debated for several decades without reaching a clear conclusion. The benefits of organized physical activity on fitness and mental health have been widely described. Indeed, by acting on specific mechanisms, physical activity can influence the physiology of several chronic conditions. It was shown to improve skeletal muscle metabolism and regeneration, neurogenesis, mitochondrial biogenesis, and antioxidant defense. Interestingly, all these pathways are involved in ALS pathology. This review will provide a broad overview of the effect of different exercise protocols on the onset and progression of ALS, both in humans and in animal models. Furthermore, we will discuss challenges and opportunities to exploit physiological responses of imposed exercise training for therapeutic purposes.

Harnessing conformational drivers in drug design.

This review article explores the pivotal role of conformational drivers in the discovery of drug-like molecules and illustrates their significance through real-life examples. Understanding molecular conformation is paramount to drug hunting as it can impact on- and off-target potency, metabolism, permeability, and solubility. Each conformational driver or effector is described and exemplified in a separate section. The final section is dedicated to NMR spectroscopy and illustrates its utility as an essential tool for conformational design.

Conceptualizing Health-Seeking Behavior among Adolescents and Youth with Substance Use Disorder in Urban KwaZulu-Natal

In a setting where substance use is rife, understanding contextual factors that influence an individual’s perceived eligibility to seek rehabilitation is paramount. The study explores how situational factors influence an individual’s perceived eligibility for healthcare uptake in people with substance use disorder (SUD). Using qualitative methods, the study draws on in-depth interviews with 20 substance users and 20 family members to unpack how individuals with SUD negotiate their eligibility for health services. Findings show that substance users are aware of their substance use habits and acknowledge their eligibility for health services with information on the navigation of health services is shared by peers and family members. Access and use of health services is hindered by individual determinants and the availability of health services for substance users, such as rehabilitation centers. The hunt for drugs and long waiting queues for health service acquisition overshadows substance users’ claim to health services. Future research should prioritize understanding substance use and health seeking behavior at a context specific level in community settings so that, even in the absence of substance use health facilities, substance use is addressed at least from a harm reduction perspective which can improve health outcomes.

PheroxyPyrabenz and Carbopyrropyridin against major proteins of SARS CoV-2: a comprehensive in-silico molecular docking and dynamics simulation studies

The pandemic that started in 2020 left us with so much information about viruses and respiratory diseases, and the cause behind it was severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The world is still recovering, which costs so many economic and other indirect disasters; despite that, no medications are available on the market. Although the WHO approved a few vaccines on an emergency basis, the remarks and the reinfection chances are still under investigation, and a few pharmaceutical companies are also claiming that a few medications can be effective. However, there is no situation in control. SARS CoV-2 mutates and comes in different forms, making the situation unpredictable. In this study, we have screened the complete Asinex’s BioDesign library, which contains 170,269 compounds, and shorted the data against the docking score that helps in the identification of 4-[5-(3-Ethoxy-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1, 2-benzenediol (PheroxyPyrabenz) and 1-[(3R,4R)-1-(5-Aminopentanoyl)-4-hydroxy-3-pyrrolidinyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide (Carbopyrropyridin) as a significant drug candidate that can work against the multiple proteins of the SARS CoV-2 resulting in seizing the complete biological process of the virus. Further, the study extended to Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics (MD) simulation of both the compounds with their complexity. The complete workflow of the study has shown satisfactory results, and both drug candidates can potentially stop the hunt for drugs against this virus after its experimental validation. Further, we checked both compounds’ absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, showing case-proof validatory results. Communicated by Ramaswamy H. Sarma

Drug hunting in chemical space

Connecting chemical building blocks allows drug hunters to explore a much bigger chemical space than before. The challenge is to narrow this field of compounds to something manageable. To do that, chemists are turning to new computational tools to navigate this increasingly huge chemical universe, and they are combining technologies. Experts say these new approaches should speed up the identification process, and industry is investing time and money to optimize the hunt. Back in 1996, a paper came out that has been cited time and time again. In a footnote to a figure caption , Regine S. Bohacek, Colin McMartin, and Wayne C. Guida of Ciba-Geigy estimated that at least 10 63 small, drug-like molecules could be produced through stitching together up to 30 carbon, nitrogen, oxygen, and sulfur atoms in different arrangements ( Med. Res. Rev. 1996 , 16 , 3). And yet a look at drugs that have

Quirks of kids’ cancers are revealed — and could shape hunt for drugs

Quirks of kids’ cancers are revealed — and could shape hunt for drugs

Pharma pumps up anti-tau Alzheimer pipeline despite first Phase III failure.

AbbVie, Bristol-Myers Squibb, Genentech, Janssen and Merck & Co. have all advanced anti-tau candidates into Phase I trials in the hunt for drugs that can modify the course of Alzheimer disease.

Solving for X: Accelerators Could Speed Search for Rare Disease Therapies

David Mott, general partner at NEA, recalls a conversation he had at a conference 5 years ago with Dr. Eric Topol, director of the Scripps Translational Science Institute. Topol described how genomics advances were already making it possible to chop up big diseases into smaller ones. What if they could create an accelerator staffed with experienced drug developers who could perform fast validation of projects—or fast kill? Mott launched Cydan in April 2013 with $16 million from NEA, Pfizer Venture Investments, and Alexandria Venture Investments. In October 2013, Lundbeckfond Ventures, and Bay City Capital led an additional $10 million financing round with the prior investors.“The way science has evolved, we are beginning to understand these diseases at a genetic and molecular level,” says Mott. “We are trying to stop disease at its beginning. It is decreasing our expenses in drug development. It is changing its expense-to-risk ratio.”According to Mott, segmenting disease into separate subtypes is already being done in cancer, as with, for example, Crizotinib, an ALK inhibitor for non-small cell lung cancer that the FDA approved in 2011. “Lung cancer is not a single cancer but many different types of cancers that affect the lung,” says Mott. “There is a big crossover between rare genetic disease and targeted therapeutics in oncology.”Cydan will screen potential candidates from academic labs and patient foundations in the US and globally. According to Mott, once a compound is selected and passes a 12 month “de-risking” program, the money is already raised and a management team is in place, saving perhaps 6–12 months of downtime that would otherwise be spent in fundraising and setting up a startup infrastructure. The accelerator focuses on the crack between academic research and getting a company staffed and funded. “I think that crack is a very fruitful place to go drug hunting,” says Mott.“Patient foundations are very interested in Cydan’s model because we can ask key development questions that can enable rigorous go/no go decisions—and have capital on the table,” says Csimma. “They like the fact that we come to the table with a very objective approach because we are not asset centric.” Cydan looks for “assets” with well-characterized genetic etiology, usually animal data, or even clinical data in a different indication. Assets would also be backed up by global registries and natural history studies from patient foundations. Assets must provide meaningful clinical benefit for an unmet need and potential for an eventual spinout and/or expanded indications. Successful candidates can then transition smoothly to series A-supported development programs. The accelerator plans to launch up to five companies in 4 years. Cydan will also introduce early stage investors and academics or foundations.A year after their daughters’ diagnosis, the Spooners continue to work with doctors, including Dr. Virginia Kimonis in the division of Genetics and Metabolism at the University of California, Irvine, to research possible trial drugs. They are considering fundraising to support research opportunities. They are also working with the UMDF (United Mitochondrial Foundation) to stay informed about any drugs or therapies that become available for their disease and/or to treat similar symptoms. “We are not sure if our disease is progressive, so we are very concerned and needing to stay aware and open for treatments and hopefully one day a cure.” writes Christy Spooner.

Biophysical and pharmacological characterization of α6-containing nicotinic acetylcholine receptors expressed in HEK293 cells

Nicotinic acetylcholine receptors (nAChR's) containing the α6 subunit (α6⁎) are putative drug targets of relevance to Parkinson's disease and nicotine addiction. However, heterologous expression of α6⁎ receptors has proven challenging which has stifled drug discovery efforts. Here, we investigate potential new avenues for achieving functional α6⁎ receptor expression. Combinations of chimeric and mutated α6, β2 and β3 subunits were co-expressed in the human HEK293 cell line and receptor expression was assessed using Ca2+-imaging (FLIPR™) and whole-cell patch-clamp electrophysiology. Transient transfections of a chimeric α6/α3 subunit construct in combination with β2 and β3V9'S gave rise to significant acetylcholine-evoked whole-cell currents. Increasing the β3V9'S:β2:α6/α3 cDNA ratio, resulted in a significantly higher fraction of cells with robust current levels. Using an excess of wild-type β3, significant functional expression of α6/α3β2β3 was also demonstrated. Comparing the acetylcholine concentration–response relationship of α6/α3β2β3V9'S to that of α6/α3β2β3 revealed the β3 point mutation to result in decreased current decay rate and increased ACh agonist potency. Ca2+-imaging experiments showed preservation of basic α6⁎ receptor pharmacology. Our results establish that α6/α3β2β3V9'S replicate several basic features of native α6⁎ receptors but also highlight several caveats associated with using this construct and may therefore provide guidance for future drug hunting efforts.

In vivo receptor occupancy assay of histamine H3 receptor antagonist in rats using non-radiolabeled tracer

IntroductionRapid and reliable preclinical receptor occupancy measurement at the target organ in relevant species is critical in accelerating the drug hunting process. The aim of this study was to develop in vivo receptor occupancy assay for histamine H3 receptors (H3R) using the non-radiolabeled GSK189254 as a tracer and to correlate the occupancy–exposure relationship for H3R antagonists in the rats. MethodsIn vivo tracer characterization studies like brain regional distribution, dose and time dependent uptake were carried out for GSK189254 in the male Wistar rats after intravenous administration. The tracer specificity was validated by pretreatment with H3 antagonists like ciproxifan, thioperamide, and GSK334429. The brain regional tracer levels and H3R antagonist concentrations in plasma and brain were quantified using liquid chromatography tandem mass spectrometry. Receptor occupancy was calculated using the ratio of total binding (striatum or frontal cortex) to the nonspecific binding (cerebellum) of the tracer in animals pretreated with H3R antagonist. ResultsHigh degree of selective distribution of GSK189254 was found in striatum, frontal cortex, and low level in the cerebellum. Regional distribution of GSK189254 in the rat brain was consistent to that of H3R distribution mapped using 3H or 11C-GSK189254 in human, porcine, and rat. The calculated occupancy ED50 values in the frontal cortex were 0.14, 1.58, and 0.14mg/kg for ciproxifan, thioperamide, and GSK334429, respectively. The plasma EC50 values (ng/mL) were found to be 2.33, 292.2, and 3.54 for ciproxifan, thioperamide and GSK334429, respectively. DiscussionResults from mass spectroscopy based approach to determine H3R occupancy in rat brain is comparable with reported radiolabeled method by scintillation spectroscopy. In conclusion, non-radiolabeled GSK189254 was successfully employed as a tracer for assessing the H3R occupancy in rats and it can be used as a preclinical tool for evaluation of novel H3R ligands in the drug discovery.

The hunt for drugs to modify Alzheimer's disease

The hunt for drugs to modify Alzheimer's disease

Fragment screening: an introduction

There are clearly many different philosophies associated with adapting fragment screening into mainstream Drug Discovery Lead Generation strategies. Scientists at Astex, for instance, focus entirely on strategies involving use of X-ray crystallography and NMR. However, AstraZeneca uses a number of different fragment screening strategies. One approach is to screen a 2000 compound fragment set (with close to "lead-like" complexity) at 100 microM in parallel with every HTS such that the data are obtained on the entire screening collection at 10 microM plus the extra samples at 100 microM; this provides valuable compound potency data in a concentration range that is usually unexplored. The fragments are then screen-specific "privileged structures" that can be searched for in the rest of the HTS output and other databases as well as having synthesis follow-up. A typical workflow for a fragment screen within AstraZeneca is shown below (Figure 24) and highlights the desirability (particularly when screening >100 microM) for NMR and X-ray information to validate weak hits and give information on how to optimise them. In this chapter, we have provided an introduction to the theoretical and practical issues associated with the use of fragment methods and lead-likeness. Fragment-based approaches are still in an early stage of development and are just one of many interrelated techniques that are now used to identify novel lead compounds for drug development. Fragment based screening has some advantages, but like every other drug hunting strategy will not be universally applicable. There are in particular some practical challenges associated with fragment screening that relate to the generally lower level of potency that such compounds initially possess. Considerable synthetic effort has to be applied for post-fragment screening to build the sort of potency that would be expected to be found from a traditional HTS. However, if there are no low-hanging fruit in a screening collection to be found by HTS then the use of fragment screening can help find novelty that may lead to a target not being discarded as intractable. As such, the approach offers some significant advantages by providing less complex molecules, which may have better potential for novel drug optimisation and by enabling new chemical space to be more effectively explored. Many literature examples that cover examples of fragment screening approaches are still at the "proof of concept" stage and although delivering inhibitors or ligands, may still prove to be unsuitable when further ADMET and toxicity profiling is done. The next few years should see a maturing of the area, and as our understanding of how the concepts can be best applied, there are likely to be many more examples of attractive, small molecule hits, leads and candidate drugs derived from the approaches described.

The pharmaceutical industry and research in 2002 and beyond.

The success of the pharmaceutical industry will continue to depend on its ability to satisfy the clinical needs of established market economies. The number and quality of new drugs emerging from development pipelines seems likely to rise due to increased research and development budgets of the merged pharmaceutical companies, efficiencies across all facets of the development process, increasing use of new technologies and availability of new targets from the ongoing work on the role of human genes in disease pathways. In addition to the traditional small-molecule drugs, the market for protein products, including monoclonal antibodies and therapeutic vaccines, is likely to expand as advances in recombinant and formulation technologies are made. Current work on relatively newer fields of pharmaceutical research, such as novel G-protein-coupled receptors, chemokines/cytokines, integrins and control of cell cycle regulation and signal transduction pathways (kinases, phosphatases and transcription factors) will lead to new drugs over the next decade. It is tempting to argue that a progressive fall in the number of new drugs in the last decade of the 20th century reflects the end of an era as companies struggle to identify any remaining quality products using old-style drug hunting practices.

Search for predictive generic model of aqueous solubility using Bayesian neural nets.

Several predictive models of aqueous solubility have been published. They have good performances on the data sets which have been used for training the models, but usually these data sets do not contain many structures similar to the structures of interest to the drug research and their applicability in drug hunting is questionable. A very diverse data set has been gathered with compounds issued from literature reports and proprietary compounds. These compounds have been grouped in a so-called literature data set I, a proprietary data set II, and a mixed data set III formed by I and II. About 100 descriptors emphasizing surface properties were calculated for every compound. Bayesian learning of neural nets which cumulates the advantages of neural nets without having their weaknesses was used to select the most parsimonious models and train them, from I, II, and III. The models were established by either selecting the most efficient descriptors one by one using a modified Gram-Schmidt procedure (GS) or by simplifying a most complete model using automatic relevance procedure (ARD). The predictive ability of the models was accessed using validation data sets as much unrelated to the training sets as possible, using two new parameters: NDD(x,ref) the normalized smallest descriptor distance of a compound x to a reference data set and CD(x,mod) the combination of NDD(x,ref) with the dispersion of the Bayesian neural nets calculations. The results show that it is possible to obtain a generic predictive model from database I but that the diversity of database II is too restricted to give a model with good generalization ability and that the ARD method applied to the mixed database III gives the best predictive model.

Bacterial genome sequencing and drug discovery

The availability of bacterial genome sequence information has opened up many new strategies for antibacterial drug hunting. There are obvious benefits for the idetification and evaluation of new drug targets, but genomic-based technology is also beginning to provide new tools for the downstream, preclinical, optimisation of compounds. The greatest benefit from these new approaches lies in the ability to examine the entire genome (or several genomes) simultaneously and in total. In this way, one potential target can be evaluated against another, and either the total effects of functional impairment can be established or the effects of a compound can be compared across species.

New antibiotic discovery, novel screens, novel targets and impact of microbial genomics

The clinical need for new classes of antibiotic continues to grow, as drug resistance erodes the efficacy of current therapies. Historically, most antibiotics were discovered by random screening campaigns, but over the past 20 years, this strategy has largely failed to deliver a sufficient range of chemical diversity to keep pace with changing clinical profiles. A more rational approach to drug hunting has been greatly potentiated by the availability of bacterial genomic information. The rapid progress in sequencing and analysis of these small, prokaryotc genomes has enabled the concomitant development of powerful new technologies that are already enhancing the potential utility of genomic information. The future promises versatile and precise tools to understand what makes a successful antibiotic and moreover the means to identify and evaluate novel classes of drug.

Hunt for drugs for haemoglobinopathies

Hunt for drugs for haemoglobinopathies

The Hunt for Drugs From Nature

The Hunt for Drugs From Nature