7196 research outputs found
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Nonclinical species sensitivity to convulsions: An IQ DruSafe consortium working group initiative
No full textClinical development of compounds that carry a convulsion liability is typically limited by safety margins based on the most sensitive nonclinical species. To better understand differences in sensitivity to drug-induced convulsion of commonly used nonclinical species, a survey was distributed amongst pharmaceutical companies through an IQ consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) resulting in convulsion-related data on 80 unique compounds from 11 companies. The lowest free drug plasma concentration at which convulsions were observed and the no observed effect level for convulsions were compared between species to determine their relative sensitivity. Additionally, data were collected on other endpoints including use of electroencephalography, premonitory signs, convulsion type, the reason why development was stopped, and the highest development phase reached. The key outcomes were: (1) the dog was most often determined to be the most sensitive species by both non-exposure and exposure-based analyses, (2) there was not a clear sensitivity ranking of other species (NHP, rat and mouse), (3) CNS symptoms were frequently present at exposures that were not associated with convulsions, but no single reliable premonitory indicator of convulsion was identified, and (4) the lack of convulsions when compounds were tested in humans in this dataset may suggest that convulsion liability is well mitigated via current drug development strategies
Antibody complementarity determining region design using high-capacity machine learning
No full textMOTIVATION: The precise targeting of antibodies and other protein therapeutics is required for their proper function and the elimination of deleterious off-target effects. Often the molecular structure of a therapeutic target is unknown and randomized methods are used to design antibodies without a model that relates antibody sequence to desired properties. RESULTS: Here, we present Ens-Grad, a machine learning method that can design complementarity determining regions of human Immunoglobulin G antibodies with target affinities that are superior to candidates derived from phage display panning experiments. We also demonstrate that machine learning can improve target specificity by the modular composition of models from different experimental campaigns, enabling a new integrative approach to improving target specificity. Our results suggest a new path for the discovery of therapeutic molecules by demonstrating that predictive and differentiable models of antibody binding can be learned from high-throughput experimental data without the need for target structural data. AVAILABILITY AND IMPLEMENTATION: Sequencing data of the phage panning experiment are deposited at NIH's Sequence Read Archive (SRA) under the accession number SRP158510. We make our code available at https://github.com/gifford-lab/antibody-2019. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online
Genetic Diversity in Drug Transporters: Impact in African Populations
No full textPolymorphisms in drug transporters, like the adenosine triposphate‒binding cassette (ABC) and solute carrier (SLC) superfamilies, may contribute to the observed diversity in drug response in African patients. This review aims to provide a comprehensive summary and analysis of the frequencies and distributions in African populations of ABC and SLC variants that affect drug pharmacokinetics (PK) and pharmacodynamics (PD). Of polymorphisms evaluated in African populations, SLCO1B1 rs4149056 and SLC22A6 rs1158626 were found at markedly higher frequencies than in non-African populations. SLCO1B1 rs4149056 was associated with reduction in rifampin exposure, which has implications for dosing this important anti-tuberculosis therapy. SLC22A6 rs1158626 was associated with increased affinity for antiretroviral drugs. Genetic diversity in SLC and ABC transporters in African populations has implications for conventional therapies, notably in tuberculosis and HIV. More PK and PD data in African populations are needed to assess potential for a different response to drugs compared with other global populations
Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband 19F NMR Based Screening
No full textFragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous available screening techniques, fluorine-detected NMR has gained immense popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library and a sample composition optimized for maximal compound number and minimal measurement time are required. Here, we introduce a comprehensive method that, for the first time, enables the efficient assembly of a high quality and highly diverse fragment library containing close to 4000 compounds which can be probed for specific target interactions in less than three days. At the core of the approach is a relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like 19F motifs in a single measurement. The bandwidth is achieved by employing novel broadband shaped pulses that were optimized using optimal control theory. We demonstrate that the method reliably identifies diverse, tractable binders and enables the very fast assessment of new target proteins for their ligandability
The effect of reduced gastric acid secretion on the gastrointestinal disposition of a ritonavir amorphous solid dispersion in fasted healthy volunteers: an in vivo - in vitro investigation
No full textThis paper summarizes efforts to (i) better understand the behavior of amorphous solid dispersions (ASDs) under real-life dosing conditions and (ii) evaluate the capability of in vitro methodologies to capture gastro-intestinal drug disposition. In a first part of the study, five healthy volunteers participated in a two-way crossover trial in which one Norvir® tablet (100 mg ritonavir) was dosed under fasted and fasted + PPI conditions. Gastrointestinal aspirates were collected from both the stomach and duodenum as a function of time to map the gastrointestinal drug disposition of the ritonavir ASD formulation and to evaluate the impact of reduced gastric acid secretion on formulation performance. In both test conditions, ritonavir was shown to supersaturate in the upper GI tract illustrating the capacity of the formulation strategy itself to generate supersaturated drug content. In parallel, in vivo test conditions were closely mimicked in a multitude of in vitro methodologies (i.e., USP II dissolution apparatus, BioGIT and TIM-1 system) with the aim to evaluate their ability to predict in vivo gastrointestinal drug disposition. The selected in vitro methodologies were found capable of qualitatively and/or quantitatively picking up trends observed in the intraluminal sampling study
The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma
No full textNeuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, a large number of these cases relapse, resulting in chemoresistant disease. After relapse there is growing evidence of p53 inactivation, which suggests a role for p53 in NB’s chemo-sensitivity. Highly mutated in other cancer types, p53 mutations in NB are rare. With p53 mutations being rare, recent work has suggested that dysregulation of the negative regulator of p53, MDM2, may be a mechanism of p53 suppression in NB. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. In vitro treatment of NB cells with MDM2 inhibitors has shown promise in increasing the expression of p53, leading to a decrease in proliferation, and increasing apoptosis. BET (Bromodomain and Extra-Terminal domain) inhibitors have also been shown to be effective in treating NB cells in vitro, decreasing MYC/MYCN expression, and resulting in increased apoptosis and differentiation. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) resulting in greater p53 activation, lower expression of MYC family proteins and a subsequent synergistic increase in NB cell death
Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach
No full textThe serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients
A sustainable 1-pot, 3-step synthesis of boscalid using ppm level Pd catalysis in water
No full textBoscalid is an active ingredient in fungicides marketed by BASF. The approach
used currently for its production is unsustainable. Herein is disclosed a 3-step route using only
water as the reaction medium, and a very low loading (700 ppm or 0.07 mol %) of costly and
endangered Pd. Furthermore, the overall, isolated yield is 83%
