Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred from findings in clinical trials, animal experiments, and molecular studies going back more than forty years. In this work we explore PSP chemical space and its relevance for the prediction of adverse drug reactions. Firstly, in silico (computational) Bayesian models for 70 PSP-related targets were built, which are able to detect 93% of the ligands binding at IC(50) < or = 10 microM at an overall correct classification rate of about 94%. Secondly, employing the World Drug Index (WDI), a model for adverse drug reactions was built directly based on normalized side-effect annotations in the WDI, which does not require any underlying functional knowledge. This is, to our knowledge, the first attempt to predict adverse drug reactions across hundreds of categories from chemical structure alone. On average 90% of the adverse drug reactions observed with known, clinically used compounds were detected, an overall correct classification rate of 92%. Drugs withdrawn from the market (Rapacuronium, Suprofen) were tested in the model and their predicted ADRs align well with known ADRs. The analysis was repeated for acetylsalicylic acid and Benperidol which are still on the market. Importantly, features of the models are interpretable and back-projectable to chemical structure, raising the possibility of rationally engineering out adverse effects. By combining PSP and ADR models new hypotheses linking targets and adverse effects can be proposed and examples for the opioid mu and the muscarinic M2 receptors, as well as for cyclooxygenase-1 are presented. It is hoped that the generation of predictive models for adverse drug reactions is able to help support early SAR to accelerate drug discovery and decrease late stage attrition in drug discovery projects. In addition, models such as the ones presented here can be used for compound profiling in all development stages.     

PLATO: A Predictive Drug Discovery Web Platform for Efficient Target Fishing and Bioactivity Profiling of Small Molecules

PLATO (Polypharmacology pLATform predictiOn) is an easy-to-use drug discovery web platform, which has been designed with a two-fold objective: to fish putative protein drug targets and to compute bioactivity values of small molecules. Predictions are based on the similarity principle, through a reverse ligand-based screening, based on a collection of 632,119 compounds known to be experimentally active on 6004 protein targets. An efficient backend implementation allows to speed-up the process that returns results for query in less than 20 s. The graphical user interface is intuitive to give practitioners easy input and transparent output, which is available as a standard report in portable document format. PLATO has been validated on thousands of external data, with performances better than those of other parallel approaches. PLATO is available free of charge (http://plato.uniba.it/ accessed on 13 April 2022).     

The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM is an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions.     

Discovery and Evaluation of New Activity-Based Probes for Serine Hydrolases

Serine hydrolases play crucial biological roles and are important therapeutic targets in many clinical applications. Activity-based protein profiling of serine hydrolases by using fluorophosphonate probes, pioneered by Cravatt and co-workers, has been a powerful tool for interrogating serine hydrolases in various biological systems. Herein, we present new phenyl phosphonate probes with an azide handle for click chemistry that offer remarkable improvements over the classical fluorophosphonate serine hydrolase activity-based probes including ease of preparation, excellent cell permeability, and distinct reactivity profiles, as controlled by the phenolate leaving group. Thus, these new activity-based serine hydrolase probes are valuable tools to further interrogate this important class of enzymes.     

Vildagliptin-Derived Dipeptidyl Peptidase 9 (DPP9) Inhibitors: Identification of a DPP8/9-Specific Lead

Vildagliptin is a marketed DPP4 inhibitor, used in the management of type 2 diabetes. The molecule also has notable DPP8/9 affinity, with some preference for DPP9. Therefore, we aimed to use vildagliptin as a starting point for selective DPP8/9 inhibitors, and to engineer out the parent compound's DPP4-affinity. In addition, we wanted to identify substructures in the obtained molecules that allow their further optimization into inhibitors with maximal DPP9 selectivity. Various 2S-cyanopyrrolidines and isoindoline were investigated as P1 residues of vildagliptin analogs. The obtained set was expanded with derivatives bearing O-substituted, N-(3-hydroxyadamantyl)glycine moieties at the P2 position. In this way, representatives were discovered with DPP8/9 potencies comparable to the parent molecule, but with overall selectivity towards DPP4, DPP2, FAP, and PREP. Furthermore, the most promising molecules in this series have a 4- to 7-fold preference for DPP9 over DPP8. Finally, a molecular dynamics study was carried out to maximize our insight into experimental selectivity data.     

Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

Racial disparities in incidence and survival exist for many human cancers. Racial disparities are undoubtedly multifactorial and due in part to differences in socioeconomic factors, access to care, and comorbidities. Within the U.S., fundamental causes of health inequalities, including socio-economic factors, insurance status, access to healthcare and screening and treatment biases, are issues that contribute to cancer disparities. Yet even these epidemiologic differences do not fully account for survival disparities, as for nearly every stage, grade and histologic subtype, survival among Black women is significantly lower than their White counterparts. To address this, we sought to investigate the proteomic profiling molecular features of endometrial cancer in order to detect modifiable and targetable elements of endometrial cancer in different racial groups, which could be essential for treatment planning. The majority of proteins identified to be significantly altered among the racial groups and that can be regulated by existing drugs or investigational agents are enzymes that regulate metabolism and protein synthesis. These drugs have the potential to improve the worse outcomes of endometrial cancer patients based on race.     

糖基环糊精衍生物的合成及其生物应用研究进展

糖蛋白能够识别糖簇分子,将其连接到具有空腔的环糊精上,通过糖蛋白与环糊精上特殊糖分子间的识别作用可将糖基环糊精衍生物包结的药物分子传递到指定的生物受体中,从而使糖基环糊精衍生物具有药物靶向性.综述了近年来糖基环糊精衍生物的合成及其生物应用研究进展.     

Influence of Composition,Humidity, and Temperature on Chemical Aging in Epoxies: A Local Study of the Interphase with Air

The developing chemical depth profile in an epoxy adhesive bulk (with varying amine content) is monitored during aging by FTIR microspectroscopy on sample cuts prepared with low angle microtomy. Three aging regimes are applied in order to separate the role of temperature and water: dried or moist air (90% rel. humidity) at 60°C and dried air at 120°C for up to 300 days. Quantitative evaluation of the IR spectra shows: thermo-oxidative aging (= dried air) is controlled by the diffusion of atmospheric oxygen. It affects a gradient region of more than 200 μm in depth. At given aging time, the depth profiles depend on temperature, humidity, and on the epoxy-amine ratio. Humidity mainly affects the IR band intensities. The plasticizing effect of water promotes the loss of small network fragments. At 120°C, autoxidation of α-CH₂ at ether and amine groups and the oxidative attack on tertiary amines dominate aging. At 60°C in dried air, these processes proceed only very slowly. In the case of amine excess, aging is extended by the additional oxidation of primary and secondary amines to carbonyls. Carbonyls undergo consecutive reactions, especially in the presence of water. Hence, increasing temperature does not simply accelerate the aging mechanisms but it reduces their selectivity and changes their hierarchy. Thus, the long-term aging behavior at moderate temperatures cannot be predicted safely from accelerated aging tests.     

Impact of effective alkali and sulfide profiling on Eucalyptus globulus kraft pulping. Selectivity of the impregnation phase and its effect on final pulping results

BACKGROUND: Eucalyptus globulus is an important wood source for paper production and, in the last few years, great efforts have been made to assess its chemical specificities and improve the kraft pulping efficiency. Despite the existence of several works concerning mostly the kinetics of E. globulus kraft pulping there is a lack of systematic studies on the initial phase of pulping as well as on the impact of effective alkali (EA) charge profiling on the kraft pulping performance of this species. The aim of the present work is to assess the effect of initial effective alkali and sulfide charges on the lignin and carbohydrates removal on the impregnation phase and to investigate the effect of EA splitting charge on the whole E. globulus pulping process efficiency. RESULTS: When the EA charge at impregnation phase increases, the amount of dissolved wood increases until it reaches a constant value of about 20%. Maximum polysaccharide removal at impregnation phase was about 10% of total wood weight. Glucose removal during impregnation was attributed to the degradation and/or dissolution of E. globulus glucans. For EA charges at impregnation phase higher than ～15%, xylan retention on wood was roughly constant. Despite the differences found at impregnation phase on the amount of dissolved wood and lignin removal, it was demonstrated that these differences are almost completely attenuated until the end of the kraft pulping process. CONCLUSION: In the case of E. globulus, for a constant effective alkali charge, alkali profiling does not affect the whole kraft pulping performance. Copyright © 2007 Society of Chemical Industry     

Chemical Proteomics for Expanding the Druggability of Human Disease

Abstract . Over the past decade, chemical proteomics has emerged as a powerful technique to understand small molecule and protein function in the physiological system and plays a key role in unravelling the cellular targets of pharmacological modulators. Chemical proteomics that integrates activity-based protein profiling (ABPP) with mass spectrometry has been introduced to evaluate small-molecule and protein interaction and expand the druggable proteome. A much larger fraction of the human proteome can now be targeted by small molecules than estimated by past predictions of protein druggability.     

Prospective Validation of a Comprehensive In silico hERG Model and its Applications to Commercial Compound and Drug Databases

Ligand‐based in silico hERG models were generated for 2 644 compounds using linear discriminant analysis (LDA) and support vector machines (SVM). As a result, the dataset used for the model generation is the largest publicly available (see Supporting Information). Extended connectivity fingerprints (ECFPs) and functional class fingerprints (FCFPs) were used to describe chemical space. All models showed area under curve (AUC) values ranging from 0.89 to 0.94 in a fivefold cross‐validation, indicating high model consistency. Models correctly predicted 80 % of an additional, external test set; Y‐scrambling was also performed to rule out chance correlation. Additionally models based on patch clamp data and radioligand binding data were generated separately to analyze their predictive ability when compared to combined models. To experimentally validate the models, 50 of the predicted hERG blockers from the Chembridge database and ten of the predicted non‐hERG blockers from an in‐house compound library were selected for biological evaluation. Out of those 50 predicted hERG blockers, tested at a concentration of 10 μM , 18 compounds showed more than 50 % displacement of [³H]astemizole binding to cell membranes expressing the hERG channel. K_i values of four of the selected binders were determined to be in the micromolar and high nanomolar range (K_i (VH 01 )=2.0 μM , K_i (VH 06 )=0.15 μM , K_i (VH 19 )=1.1 μM and K_i (VH 47 )=18 μM ). Of these four compounds, VH 01 and VH 47 showed also a second, even higher affinity binding site with K_i values of 7.4 nM and 36 nM , respectively. In the case of non‐hERG blockers, all ten compounds tested were found to be inactive, showing less than 50 % displacement of [³H]astemizole binding at 10 μM . These experimentally validated models were then used to virtually screen commercial compound databases to evaluate whether they contain hERG blockers. 109 784 (23 %) of Chembridge, 133 175 (38 %) of Chemdiv, 111 737 (31 %) of Asinex and 11 116 (18 %) of the Maybridge database were predicted to be hERG blockers by at least two of the models, a prediction which could, for example, be used as a pre‐filtering tool for compounds with potential hERG liabilities.     

Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14⁺⁺CD16⁺ monocytes, CD56⁺ CD16^dim natural killer cells, marginal zone-like IgD⁺CD27⁺ B cells, and on CD4⁺ and CD8⁺ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.     

毛细管电泳技术及其在药物分析中的应用

对毛细管电泳在药物中的分离测定,手性药物的拆分及药物中杂质含量的测定做了综述,并列举了部分手性药物拆分的应用实例。     

Determination of external surface composition of zeolite particles by synchrotron radiation XPS

Non-destructive depth profiling analysis with high surface sensitivity was performed by XPS with synchrotron radiation excitation. Comparison of the measured atomic ratios with the simulated ones revealed the presence of a thin Al- and Na-rich overlayer at the external surface of NaY particles. For HY zeolite particles, a gradual decrease in the Al/Si ratio from the external surface to the bulk was observed.     

Depth profiling of coil coating using step-scan photoacoustic FTIR

Photoacoustic (PA) Fourier Transform Infrared Spectroscopy (FTIR) has been demonstrated to be very useful in the analysis of molecular distribution and/or degradation in polymeric materials in a non-destructive manner. Step-scan (SS) PA FTIR has been found to be especially suitable to depth profile multi-layered polymer coating/laminate systems. In this current study, the capability of SSPA-FTIR in assessing industrial coil coatings was evaluated. Two multi-layered model coil coating samples were prepared, one had a pigmented Polyvinylidene Fluoride (PVdF) top coat and the other had a clear Polyethylene Terephthalate (PET) laminate film on the surface; both were depth profiled by SSPA-FTIR. The signal magnitude and phase angle were used to obtain a modulation frequency and a phase angle resolved depth profile, respectively. The advantages and disadvantages of the technique were also investigated. Optical microscopy was used to determine the true thicknesses of the PET and PVdF layers from the sample cross-sections. The values were compared with those predicted by SSPA-FTIR. It was found that a precise depth profile was only obtained with the PET sample whereas in the high pigmented coating system, the predicted values were smaller than the true PVdF thickness, possibly due to the high thermal diffusivity of the inorganic pigment.     

The Discovery and Structure-Activity Evaluation of (+)-Floyocidin B and Synthetic Analogs

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug-resistant M. tuberculosis makes the discovery of novel anti-tuberculosis active structures an urgent priority. Here, we show that (+)-floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus-derived natural products, displays promising antitubercular hit properties. (+)-Floyocidin B was identified by activity-guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X-ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)-floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure-activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.     

Detection of Novel Carbohydrate-Related Compounds in Aqueous Samples Using a Capillary Electrophoretic Profiling Method

The aim of this research was to extend an existing capillary electrophoresis (CE) method, originally developed for the determination of mono- and disaccharides, to the determination of alternative carbohydrate compounds, namely furfural and polydatin. Empirical validation confirms that this novel method can be applied for the determination of analyte concentrations from complex matrices, and the evaluation of their carbohydrate composition. It is concluded that the approach has validity as an analytical procedure and has the ability to determine industrially important analytes from a heterogeneous biological sample matrix, and thus, the method adds value to the development of large scale separation processes. However, some additional optimization is required before online applications.     

Recent advances in stratification and film formation of latex films; attenuated total reflection and step-scan photoacoustic FTIR spectroscopic studies

Surfactant–latex molecular level interactions as well as transient effects during latex film formation play an important role in latex technology. This review article focuses on the siloxane effects on anionic sodium dioctylsulfosuccinate (SDOSS) surfactant exudation during latex coalescence and quantitative analysis of SDOSS distribution at the both film–air (F–A) and film–substrate (F–S) interfaces. Attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy was utilized for characterization of the interactions between SDOSS and styrene–butyl acrylate latex copolymers. In addition, studies of SDOSS stratification along with depth-profiling analysis during latex film formation utilizing step-scan photoacoustic (S²-PAS) FTIR spectroscopy illustrate that SDOSS content is enriched at the F–A interface and decreases as the penetration depth increases across the latex film thickness. © 1998 John Wiley & Sons, Inc. J. Appl. Polym. Sci. 70: 1321–1348, 1998     

Depth profiling of clear coil coating by confocal Raman microscopy

Confocal Raman microscopy (CRM) has been demonstrated to be very effective in the analysis of the distribution of chemical moieties within polymeric coil coatings. To verify the compatibility of CRM with commercial coil coatings, a multi-layer coil coating system was prepared and depth profiled by CRM with both dry and immersion oil objectives (non-destructive method). The cross-section of the same sample was then scanned by CRM (destructive method). It was found that the CRM depth profiling resolution was affected by both the intrinsic and extrinsic factors of the objective lens. The use of an immersion oil objective improved depth resolution and minimised the refraction effect, however the oil contaminated the coating surface. The dry method yielded the lowest depth resolution but was completely non-destructive. The CRM lateral scanning of the sample cross-section yielded the most accurate depth profile information; however, the destructive nature of this method is a major disadvantage. It was also found that pigments incorporated in the coil coating formulation affected the CRM depth profiling accuracy due to the strong Raman scattering of these materials.