Longitudinal consumption of fruits and vegetables and risk of asthma by 5 years of age.

BACKGROUND: Fruit and vegetable consumption has been linked to a decreased risk of asthma, but prospective evidence on longitudinal consumption in childhood is scarce. We aimed to investigate the association between fruit and vegetable consumption in childhood and the risk of asthma by the age of 5 years, and to explore the role of processing of fruits and vegetables in the Finnish Type 1 Diabetes Prediction and Prevention Allergy Study. METHODS: Child's food consumption was assessed by 3-day food records completed at the age of 3 and 6 months, and 1, 2, 3, 4, and 5 years, and asthma and allergies by a validated modified version of the ISAAC questionnaire at the age of 5 years. Consumption of processed and unprocessed fruits and vegetables was calculated. Joint models with a current value association structure for longitudinal and time-to-event data were used for statistical analyses. RESULTS: Of the 3053 children, 184 (6%) developed asthma by the age of 5 years. The risk of asthma was not associated with the consumption of all fruits and vegetables together (HR 1.00, 95%CI 0.99-1.01 per consumption of 1 g/MJ, adjusted for energy and other covariates), or with most subgroups. Weak inverse associations were seen between all leafy vegetables and asthma (HR = 0.87, 0.77-0.99), and unprocessed vegetables and nonatopic asthma (HR = 0.90, 95% CI 0.81-0.98). CONCLUSION: Total consumption of fruits and vegetables in childhood was not associated with the development of asthma by the age of 5 years. Weak inverse associations found for vegetables need to be confirmed or rejected in future studies.

Dietary fatty acid intake in childhood and the risk of islet autoimmunity and type 1 diabetes: the DIPP birth cohort study.

PURPOSE: The aim was to study the associations between dietary intake of fatty acids in childhood and the risk of islet autoimmunity and type 1 diabetes (T1D). METHODS: The prospective Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study included children with genetic susceptibility to T1D born between 1996 and 2004. Participants were followed up every 3 to 12 months up to 6 years for diet, islet autoantibodies, and T1D. Dietary intake of several fatty acids at the age of 3 months to 6 years was assessed 1-8 times per participant with a 3-day food record. Joint models adjusted for energy intake, sex, HLA genotype and familial diabetes were used to investigate the associations of longitudinal intake of fatty acids and the development of islet autoimmunity and T1D. RESULTS: During the 6-year follow-up, 247 (4.4%) children of 5626 developed islet autoimmunity and 94 (1.7%) children of 5674 developed T1D. Higher intake of monounsaturated fatty acids (HR 0.63; 95% CI 0.47, 0.82), arachidonic acid (0.69; 0.50, 0.94), total n-3 fatty acids (0.64; 0.48, 0.84), and long-chain n-3 fatty acids (0.14; 0.04, 0.43), was associated with a decreased risk of islet autoimmunity with and without energy adjustment. Higher intake of total fat (0.73; 0.53, 0.98), and saturated fatty acids (0.55; 0.33, 0.90) was associated with a decreased risk of T1D only when energy adjusted. CONCLUSION: Intake of several fatty acids was associated with a decreased risk of islet autoimmunity or T1D among high-risk children. Our findings support the idea that dietary factors, including n-3 fatty acids, may play a role in the disease process of T1D.

Pharmacogenetics of warfarin and healthcare costs - Real-world data analysis.

PURPOSE: Variants in CYP2C9 and VKORC1 genes have been associated with individuals' sensitivity to warfarin. The aim of this study was to investigate the differences of healthcare costs of genetically normal and genetically sensitive warfarin responder groups. METHODS: This was a retrospective study linking genotype data from three Finnish biobanks (THL Biobank, Auria Biobank, Helsinki Biobank) with healthcare encounter data of the Finnish Institute of Health and Welfare (THL), drug dispensation data from the Social Insurance Institution of Finland (Kela) and laboratory data from Finnish hospital districts and municipalities. We compared the normal and sensitive warfarin responder groups in terms of healthcare costs related to bleeding and thromboembolic events, INR tests and medication purchases. RESULTS: We found a trend towards increased bleeding-related hospital costs in the sensitive warfarin responder group (881 patients) when compared with the normal responders (1627 patients) with a per patient difference of 150.9 €/year (95% CI: -55.1, 414.6 €/year, p = 0.087). INR test costs were higher in the sensitive responder group with a difference of 7.2 €/year (95% CI: -1.5, 16.4 €/year, p = 0.047). Medication costs were significantly lower in the sensitive responder group with a difference of -14.4 €/year (95% CI: -15.8, -12.9 €/year, p < 0.001). CONCLUSIONS: The difference in the costs of bleeding-related hospitalization between genetically sensitive and normal warfarin responders may justify genotype-guided warfarin dosing. Further studies with larger sample sizes would be needed to verify the result.

Integrating data from multiple Finnish biobanks and national health-care registers for retrospective studies: Practical experiences.

Aim: This case study aimed to investigate the process of integrating resources of multiple biobanks and health-care registers, especially addressing data permit application, time schedules, co-operation of stakeholders, data exchange and data quality. Methods: We investigated the process in the context of a retrospective study: Pharmacogenomics of antithrombotic drugs (PreMed study). The study involved linking the genotype data of three Finnish biobanks (Auria Biobank, Helsinki Biobank and THL Biobank) with register data on medicine dispensations, health-care encounters and laboratory results. Results: We managed to collect a cohort of 7005 genotyped individuals, thereby achieving the statistical power requirements of the study. The data collection process took 16 months, exceeding our original estimate by seven months. The main delays were caused by the congested data permit approval service to access national register data on health-care encounters. Comparison of hospital data lakes and national registers revealed differences, especially concerning medication data. Genetic variant frequencies were in line with earlier data reported for the European population. The yearly number of international normalised ratio (INR) tests showed stable behaviour over time. Conclusions: A large cohort, consisting of versatile individual-level phenotype and genotype data, can be constructed by integrating data from several biobanks and health data registers in Finland. Co-operation with biobanks is straightforward. However, long time periods need to be reserved when biobank resources are linked with national register data. There is a need for efforts to define general, harmonised co-operation practices and data exchange methods for enabling efficient collection of data from multiple sources.

A cross-industry collaboration to assess if acute oral toxicity (Q)SAR models are fit-for-purpose for GHS classification and labelling.

This study assesses whether currently available acute oral toxicity (AOT) in silico models, provided by the widely employed Leadscope software, are fit-for-purpose for categorization and labelling of chemicals. As part of this study, a large data set of proprietary and marketed compounds from multiple companies (pharmaceutical, plant protection products, and other chemical industries) was assembled to assess the models' performance. The absolute percentage of correct or more conservative predictions, based on a comparison of experimental and predicted GHS categories, was approximately 95%, after excluding a small percentage of inconclusive (indeterminate or out of domain) predictions. Since the frequency distribution across the experimental categories is skewed towards low toxicity chemicals, a balanced assessment was also performed. Across all compounds which could be assigned to a well-defined experimental category, the average percentage of correct or more conservative predictions was around 80%. These results indicate the potential for reliable and broad application of these models across different industrial sectors. This manuscript describes the evaluation of these models, highlights the importance of an expert review, and provides guidance on the use of AOT models to fulfill testing requirements, GHS classification/labelling, and transportation needs.

Frequency of Self-Weighing and Weight Change: Cohort Study With 10,000 Smart Scale Users.

BACKGROUND: Frequent self-weighing is associated with successful weight loss and weight maintenance during and after weight loss interventions. Less is known about self-weighing behaviors and associated weight change in free-living settings. OBJECTIVE: This study aimed to investigate the association between the frequency of self-weighing and changes in body weight in a large international cohort of smart scale users. METHODS: This was an observational cohort study with 10,000 randomly selected smart scale users who had used the scale for at least 1 year. Longitudinal weight measurement data were analyzed. The association between the frequency of self-weighing and weight change over the follow-up was investigated among normal weight, overweight, and obese users using Pearson's correlation coefficient and linear models. The association between the frequency of self-weighing and temporal weight change was analyzed using linear mixed effects models. RESULTS: The eligible sample consisted of 9768 participants (6515/9768, 66.7% men; mean age 41.5 years; mean BMI 26.8 kg/m2). Of the participants, 4003 (4003/9768, 41.0%), 3748 (3748/9768, 38.4%), and 2017 (2017/9768, 20.6%) were normal weight, overweight, and obese, respectively. During the mean follow-up time of 1085 days, the mean weight change was -0.59 kg, and the mean percentage of days with a self-weigh was 39.98%, which equals 2.8 self-weighs per week. The percentage of self-weighing days correlated inversely with weight change, r=-0.111 (P<.001). Among normal weight, overweight, and obese individuals, the correlations were r=-0.100 (P<.001), r=-0.125 (P<.001), and r=-0.148 (P<.001), respectively. Of all participants, 72.5% (7085/9768) had at least one period of ≥30 days without weight measurements. During the break, weight increased, and weight gains were more pronounced among overweight and obese individuals: 0.58 kg in the normal weight group, 0.93 kg in the overweight group, and 1.37 kg in the obese group (P<.001). CONCLUSIONS: Frequent self-weighing was associated with favorable weight loss outcomes also in an uncontrolled, free-living setting, regardless of specific weight loss interventions. The beneficial associations of regular self-weighing were more pronounced for overweight or obese individuals.

Skin sensitization in silico protocol.

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.

Characterization and Correction of Bias Due to Nonparticipation and the Degree of Loyalty in Large-Scale Finnish Loyalty Card Data on Grocery Purchases: Cohort Study.

BACKGROUND: To date, the evaluation of diet has mostly been based on questionnaires and diaries that have their limitations in terms of being time and resource intensive, and a tendency toward social desirability. Loyalty card data obtained in retailing provides timely and objective information on diet-related behaviors. In Finland, the market is highly concentrated, which provides a unique opportunity to investigate diet through grocery purchases. OBJECTIVE: The aims of this study were as follows: (1) to investigate and quantify the selection bias in large-scale (n=47,066) loyalty card (LoCard) data and correct the bias by developing weighting schemes and (2) to investigate how the degree of loyalty relates to food purchases. METHODS: Members of a loyalty card program from a large retailer in Finland were contacted via email and invited to take part in the study, which involved consenting to the release of their grocery purchase data for research purposes. Participants' sociodemographic background was obtained through a web-based questionnaire and was compared to that of the general Finnish adult population obtained via Statistics Finland. To match the distributions of sociodemographic variables, poststratification weights were constructed by using the raking method. The degree of loyalty was self-estimated on a 5-point rating scale. RESULTS: On comparing our study sample with the general Finnish adult population, in our sample, there were more women (65.25%, 30,696/47,045 vs 51.12%, 2,273,139/4,446,869), individuals with higher education (56.91%, 20,684/36,348 vs 32.21%, 1,432,276/4,446,869), and employed individuals (60.53%, 22,086/36,487 vs 52.35%, 2,327,730/4,446,869). Additionally, in our sample, there was underrepresentation of individuals aged under 30 years (14.44%, 6,791/47,045 vs 18.04%, 802,295/4,446,869) and over 70 years (7.94%, 3,735/47,045 vs 18.20%, 809,317/4,446,869), as well as retired individuals (23.51%, 8,578/36,487 vs 31.82%, 1,414,785/4,446,869). Food purchases differed by the degree of loyalty, with higher shares of vegetable, red meat & processed meat, and fat spread purchases in the higher loyalty groups. CONCLUSIONS: Individuals who consented to the use of their loyalty card data for research purposes tended to diverge from the general Finnish adult population. However, the high volume of data enabled the inclusion of sociodemographically diverse subgroups and successful correction of the differences found in the distributions of sociodemographic variables. In addition, it seems that food purchases differ according to the degree of loyalty, which should be taken into account when researching loyalty card data. Despite the limitations, loyalty card data provide a cost-effective approach to reach large groups of people, including hard-to-reach population subgroups.

The digital patient journey solution for patients undergoing elective hip and knee arthroplasty: Protocol for a pragmatic randomized controlled trial.

AIM: To describe a randomized controlled trial (RCT) protocol that will evaluate the effectiveness of a digital patient journey (DPJ) solution in improving the outcomes of patients undergoing total hip and knee arthroplasty. BACKGROUND: There is an urgent need for novel technologies to ensure sustainability, improve patient experience, and empower patients in their own care by providing information, support, and control. DESIGN: A pragmatic RCT with two parallel arms. METHODS: The participants randomized assigned to the intervention arm (N = 33) will receive access to the DPJ solution. The participants in the control arm (N = 33) will receive conventional care, which is provided face to face by using paper-based methods. The group allocations will be blinded from the study nurse during the recruitment and baseline measures, as well as from the outcome assessors. Patients with total hip arthroplasty will be followed up for 8-12 weeks, whereas patients with total knee arthroplasty will be followed up for 6-8 weeks. The primary outcome is health-related quality of life, measured by the EuroQol EQ-5D-5L scale. Secondary outcomes include functional recovery, pain, patient experience, and self-efficacy. The first results are expected to be submitted for publication in 2020. IMPACT: This study will provide information on the health effects and cost benefits of using the DPJ solution to support a patient's preparation for surgery and postdischarge surgical care. If the DPJ solution is found to be effective, its implementation into clinical practice could lead to further improvements in patient outcomes. If the DPJ solution is found to be cost effective for the hospital, it could be used to improve hospital resource efficiency.

Safety of Algal Oil Containing EPA and DHA in cats during gestation, lactation and growth.

Algal Oil Containing EPA and DHA (AOCED) at approximately 50% was developed as a sustainable n-3 fatty acid source. AOCED was incorporated in diets at dose levels of 0%, 0.75%, 1.5% and 3.0% (w/w) and administered to healthy domestic shorthair female cats starting two weeks before mating, then during mating, gestation, lactation and to their kittens until they reached 32 weeks of age. The diets were made isocaloric and met the Association of American Feed Control Officials (AAFCO) nutrient requirements of cats for growth and reproduction. Dietary AOCED treatment did not affect the overall health, physiological parameters, food consumption and body weights of the queens and their kittens. No AOCED-related changes in haematology, coagulation or clinical chemistry parameters were observed in either generation when compared to control cats. Plasma levels of EPA and DHA were dose-dependently increased in both generations, demonstrating bioavailability of the fatty acids. In this study, safety of AOCED at levels up to 3.0% in the diet was demonstrated in cats with administration starting in utero and until kittens reached 32 weeks of age. Bioavailability of EPA and DHA in cats supports use of AOCED as a source of EPA and DHA for feline growth and reproduction.

Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11ß-hydroxysteroid dehydrogenase 1.

The enzyme 11ß-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11ß-HSD1 is an attractive intervention strategy and the discovery of novel selective 11ß-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11ß-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC50 below 400 nM) that were inactive at 1 µM concentration against structurally related enzymes (11ß-HSD2, 17ß-HSD1 and 17ß-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.

Making reliable negative predictions of human skin sensitisation using an in silico fragmentation approach.

A previously published fragmentation method for making reliable negative in silico predictions has been applied to the problem of predicting skin sensitisation in humans, making use of a dataset of over 2750 chemicals with publicly available skin sensitisation data from 18 in vivo assays. An assay hierarchy was designed to enable the classification of chemicals within this dataset as either sensitisers or non-sensitisers where data from more than one in vivo test was available. The negative prediction approach was validated internally, using a 5-fold cross-validation, and externally, against a proprietary dataset of approximately 1000 chemicals with in vivo reference data shared by members of the pharmaceutical, nutritional, and personal care industries. The negative predictivity for this proprietary dataset was high in all cases (>75%), and the model was also able to identify structural features that resulted in a lower accuracy or a higher uncertainty in the negative prediction, termed misclassified and unclassified features respectively. These features could serve as an aid for further expert assessment of the negative in silico prediction.

Correlation between symptoms and functioning in psychiatric patients and temporal patterns of medication refills derived from pharmacy prescription claims.

OBJECTIVES:: Pharmacy dispensing claims data provide longitudinal records of prescriptions and refill events. Previous studies in psychiatric patients have utilised these data to derive indicators of medication adherence based on information regarding the amount of medication supplied and its dosage. An alternative approach was developed in which the regularity of medication refill events was analysed as a potential indicator of psychiatric patient symptoms and functioning. METHODS:: A method to quantify the regularity of medication refills was developed and subsequently used to investigate how the resulting regularity index (RI), derived from retrospective prescription refill records, correlated with symptomatic and functional assessments of 89 psychiatric patients after adjusting for covariates. RESULTS:: A two-step hierarchical regression model indicated that variances explained by prior hospitalisation and the RI were significant for patient scores on the Kessler 10 Psychological Distress Scale (K10), standard beta value 0.22, p < 0.05, for the SF-12 MC, standard beta value -0.31, p < 0.01, and the Work and Social Adjustment Scale (WSAS), standard beta value 0.31, p < 0.01. CONCLUSIONS:: This method to quantify the regularity of medication refills using prescription supply date alone may provide valuable information about patients' symptoms and functioning.

Phenylbenzenesulfonates and -sulfonamides as 17ß-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis.

17ß-Hydroxysteroid dehydrogenase type 2 (17ß-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17ß-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17ß-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17ß-HSD2 inhibitors have been reported. Our previous work led to the identification of phenylbenzenesulfonamides and -sulfonates as new 17ß-HSD2 inhibitors by ligand-based pharmacophore modeling and virtual screening. In this study, new molecules representing this scaffold were synthesized and tested in vitro for their 17ß-HSD2 activity to derive more profound structure-activity relationship rules.

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17ß-Hydroxysteroid Dehydrogenase Type 2.

17ß-Hydroxysteroid dehydrogenase type 2 (17ß-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17ß-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17ß-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17ß-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 µM, (-)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 µM, isoliquiritigenin (6), IC50 0.36 ± 0.08 µM, and ethyl vanillate (12), IC50 1.28 ± 0.26 µM, showed 8-fold or higher selectivity over 17ß-HSD1. As some of the identified compounds belong to the same structural class, structure-activity relationships were derived for these molecules. Thus, this study describes new 17ß-HSD2 inhibitors from nature and provides insights into the binding pocket of 17ß-HSD2, offering a promising starting point for further research in this area.

Applicability of in silico genotoxicity models on food and feed ingredients.

Evaluation of the genotoxic potential of food and feed ingredients is required in the development of new substances and for their registration. In addition to in vitro and in vivo assays, in silico tools such as expert alert-based and statistical models can be used for data generation. These in silico models are commonly used among the pharmaceutical industry, whereas the food industry has not widely adopted them. In this study, the applicability of in silico tools for predicting genotoxicity was evaluated, with a focus on bacterial mutagenicity, in vitro and in vivo chromosome damage assays. For this purpose, a test set of 27 food and feed ingredients including vitamins, carotenoids, and nutraceuticals with experimental genotoxicity data was constructed from proprietary data. This dataset was run through multiple models and the model applicability was analyzed. The compounds were generally within the applicability domain of the models and the models predicted the compounds correctly in most of the cases. Although the regulatory acceptance of in silico tools as single data source is still limited, the models are applicable and can be used in the safety evaluation of food and feed ingredients.

Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17ß-Hydroxysteroid Dehydrogenases.

Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17ß-hydroxysteroid dehydrogenase (17ß-HSD) 1 and the estrogen-inactivating 17ß-HSD2. A ligand-based 17ß-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17ß-HSD1 and 17ß-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite p-hydroxybenzoic acid, inhibited 17ß-HSD2. Ethylparaben and ethyl vanillate inhibited 17ß-HSD2 with IC50 values of 4.6 ± 0.8 and 1.3 ± 0.3 µM, respectively. Additionally, parabens size-dependently inhibited 17ß-HSD1, whereby hexyl- and heptylparaben were most active with IC50 values of 2.6 ± 0.6 and 1.8 ± 0.3 µM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17ß-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17ß-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive p-hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo.

Leoligin, the major lignan from Edelweiss, inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase and reduces cholesterol levels in ApoE-/- mice.

The health benefit through the control of lipid levels in hyperlipidaemic individuals is evident from a large number of studies. The pharmacological options to achieve this goal shall be as specific and personalized as the reasons for and co-factors of hyperlipidaemia. It was the goal of this study to reveal the impact of leoligin on cholesterol levels and to define its mechanism of action. Oral application of leoligin in ApoE-/- mice led to significantly reduced total serum cholesterol levels and a reduction in postprandial blood glucose peak levels. In the absence of biochemical signs of toxicity, leoligin treatment resulted in reduced weight gain in mice. The effects of leoligin on serum cholesterol levels may be due to a direct inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) by a unique, non-statin-like binding mode. Postprandial serum glucose peaks may be reduced by a mild peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonistic activity of leoligin. No effect on atherosclerotic plaque size was observed. As a non-toxic, cholesterol-, peak glucose-, and weight gain-lowering compound, leoligin continues to fulfil characteristics of a potential agent for the treatment of cardiovascular disease (CVD). The counterregulatory overexpression of hepatic HMGCR in leoligin treated animals possibly explains the missing permanent anti-atherosclerotic effect.

Methods for generating and applying pharmacophore models as virtual screening filters and for bioactivity profiling.

Biological effects of small molecules in an organism result from favorable interactions between the molecules and their target proteins. These interactions depend on chemical functionalities, bonds, and their 3D-orientations towards each other. These 3D-arrangements of chemical functionalities that make a small molecule active towards its target can be described by pharmacophore models. In these models, chemical functionalities are represented as so-called features. Commonly, they are obtained either from a set of active compounds or directly from the observed protein-ligand interactions as present in X-ray crystal structures, NMR structures, or docking poses. In this review, we explain the basics of pharmacophore modeling including dataset generation, 3D-representations and conformational analysis of small molecules, pharmacophore model construction, model validation, and its benefits to virtual screening and other applications.