Systems biology in drug discovery Butcher, Eugene C; Berg, Ellen L; Kunkel, Eric J
Nature biotechnology,
10/2004, Letnik:
22, Številka:
10
Journal Article
Recenzirano
The hope of the rapid translation of 'genes to drugs' has foundered on the reality that disease biology is complex, and that drug development must be driven by insights into biological responses. ...Systems biology aims to describe and to understand the operation of complex biological systems and ultimately to develop predictive models of human disease. Although meaningful molecular level models of human cell and tissue function are a distant goal, systems biology efforts are already influencing drug discovery. Large-scale gene, protein and metabolite measurements ('omics') dramatically accelerate hypothesis generation and testing in disease models. Computer simulations integrating knowledge of organ and system-level responses help prioritize targets and design clinical trials. Automation of complex primary human cell-based assay systems designed to capture emergent properties can now integrate a broad range of disease-relevant human biology into the drug discovery process, informing target and compound validation, lead optimization, and clinical indication selection. These systems biology approaches promise to improve decision making in pharmaceutical development.
Recent evidence suggests that legal marijuana markets in several U.S. states have decreased violence in Mexican-U.S. border regions. As legal markets for production and distribution displace drug ...cartel distribution, the violence associated with cartel trafficking and distribution decreases. Prior analysis has not considered an important emerging innovation for drug distribution: online anonymous marketplaces. The increasing volume of drug trade that has occurred on this “Dark Web” could result in reduced drug cartel violence as production and distribution use this substitute network and turn away from the cartel distribution networks. This paper investigates the relationship between border violence and the volume of drug trade that occurs on the Dark Web using a difference in differences model. We examine differences in crime rates at the U.S.-Mexico border and away from the border during the emergence of the Dark Web. Data on Dark Web transactions, users, and markets allows us to measure changes in Dark Web activity and the subsequent impact on crime. We find evidence that the rise in Dark Web marketplaces results in crime reductions at the border of the U.S., relative to non-border counties.
Since the cloning of the histamine H(3) receptor cDNA in 1999 by Lovenberg and co-workers, this histamine receptor has gained the interest of many pharmaceutical companies as a potential drug target ...for the treatment of various important disorders, including obesity, attention-deficit hyperactivity disorder, Alzheimer's disease, schizophrenia, as well as for myocardial ischaemia, migraine and inflammatory diseases. Here, we discuss relevant information on this target protein and describe the development of various H(3) receptor agonists and antagonists, and their effects in preclinical animal models.
Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve ...clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.
The poetry of Anelisa Thengimfene, through scholarly critique, certifies that applicatory subjects may be enacted in isiXhosa modern literature. Such applicatory subjects breathe pertinence to social ...issues that predominantly affect the South African youth and other organs of social anatomy. Using Anelisa Thengimfene's two selected isiXhosa poems (Imfundo andIziyobisi) , issues concerning education and drug abuse are critiqued in terms of content or subject matter in order to unmask their interfacing meanings. Textual analysis alongside qualitative research methodology is appointed to operate in a synergetic relationship. The principal objective of this article is to exhibit that education and drug addiction are social problems that continue to sabotage the lives of many young men and women in South Africa and elsewhere. The findings and discussions underscore that isiXhosa modern literature should be employed for the fact that it contests contemporary issues that are valuable and worth theoretical and practical debates. As a direct consequence of that, the closing remarks recommend a maintained scrutinisation of isiXhosa modern poetry. The contribution of this intellectual discourse can be pinned on the fact that Anelisa Thengimfene is an emerging isiXhosa literary writer, and therefore, new insights can be enacted from her literary art.
High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like: they act noncompetitively, show little ...relationship between structure and activity, and have poor selectivity. Attempts to develop these peculiar molecules into viable leads are often futile, and much time can be wasted on the characterization of these “phony” hits. Despite their common occurrence, the mechanism of action of these promiscuous molecules remains unknown. To investigate this problem, 45 diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of various receptors, including β-lactamase, malarial protease, dihydrofolate reductase, HIV Tar RNA, thymidylate synthase, kinesin, insulin receptor, tyrosine kinases, farnesyltransferase, gyrase, prions, triosephosphate isomerase, nitric oxide synthase, phosphoinositide 3-kinase, and integrase; 30 were from an in-house screening library of a major pharmaceutical company. In addition to their original targets, 35 of these 45 compounds were shown to inhibit several unrelated model enzymes. These 35 screening hits included compounds, such as fullerenes, dyes, and quercetin, that have repeatedly shown activity against diverse targets. When tested against the model enzymes, the compounds showed time-dependent but reversible inhibition that was dramatically attenuated by albumin, guanidinium, or urea. Surprisingly, increasing the concentration of the model enzymes 10-fold largely eliminated inhibition, despite a 1000-fold excess of inhibitor; a well-behaved competitive inhibitor did not show this behavior. One model to explain these observations was that the active form of the promiscuous inhibitors was an aggregate of many individual molecules. To test this hypothesis, light scattering and electron microscopy experiments were performed. The nonspecific inhibitors were observed to form particles of 30−400 nm diameter by both techniques. In control experiments, a well-behaved competitive inhibitor and an inactive dye-like molecule were not observed to form aggregates. Consistent with the hypothesis that the aggregates are the inhibitory species, the particle size and IC50 values of the promiscuous inhibitors varied monotonically with ionic strength; a competitive inhibitor was unaffected by changes in ionic strength. Unexpectedly, aggregate formation appears to explain the activity of many nonspecific inhibitors and may account for the activity of many promiscuous screening hits. Molecules acting via this mechanism may be widespread in drug discovery screening databases. Recognition of these compounds may improve screening results in many areas of pharmaceutical interest.
This paper examines the causal effect of earning a GED or vocational degree on future illicit drug use, employing random assignment into the United States' most comprehensive education and vocational ...training program for at-risk youth - Job Corps - as a source of exogenous variability in degree attainment. Nonparametric bounds under relatively weak monotonicity assumptions are constructed to allow the random assignment to violate the exclusion restriction when used as an instrument. We also use a fixed effect model and propensity score weighting to supplement the results. The results from different methods suggest that degree attainment may have the most significant effect in reducing the illicit drug use of blacks, while the results for whites and Hispanics are less conclusive.
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