97 research outputs found

    Review of QSAR Models and Software Tools for predicting Biokinetic Properties

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    In the assessment of industrial chemicals, cosmetic ingredients, and active substances in pesticides and biocides, metabolites and degradates are rarely tested for their toxicologcal effects in mammals. In the interests of animal welfare and cost-effectiveness, alternatives to animal testing are needed in the evaluation of these types of chemicals. In this report we review the current status of various types of in silico estimation methods for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their metabolites/degradation products. The review was performed in a broad sense, with emphasis on QSARs and rule-based approaches and their applicability to estimation of oral bioavailability, human intestinal absorption, blood-brain barrier penetration, plasma protein binding, metabolism and. This revealed a vast and rapidly growing literature and a range of software tools. While it is difficult to give firm conclusions on the applicability of such tools, it is clear that many have been developed with pharmaceutical applications in mind, and as such may not be applicable to other types of chemicals (this would require further research investigation). On the other hand, a range of predictive methodologies have been explored and found promising, so there is merit in pursuing their applicability in the assessment of other types of chemicals and products. Many of the software tools are not transparent in terms of their predictive algorithms or underlying datasets. However, the literature identifies a set of commonly used descriptors that have been found useful in ADME prediction, so further research and model development activities could be based on such studies.JRC.DG.I.6-Systems toxicolog

    Identification of Potential New Aedes aegypti Juvenile Hormone Inhibitors from N-Acyl Piperidine Derivatives: A Bioinformatics Approach

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    Aedes aegypti mosquitoes transmit several human pathogens that cause millions of deaths worldwide, mainly in Latin America. The indiscriminate use of insecticides has resulted in the development of species resistance to some such compounds. Piperidine, a natural alkaloid isolated from Piper nigrum, has been used as a hit compound due to its larvicidal activity against Aedes aegypti. In the present study, piperidine derivatives were studied through in silico methods: pharmacophoric evaluation (PharmaGist), pharmacophoric virtual screening (Pharmit), ADME/Tox prediction (Preadmet/Derek 10.0 (R)), docking calculations (AutoDock 4.2) and molecular dynamics (MD) simulation on GROMACS-5.1.4. MP-416 and MP-073 molecules exhibiting Delta G binding (MMPBSA -265.95 +/- 1.32 kJ/mol and -124.412 +/- 1.08 kJ/mol, respectively) and comparable to holo (Delta G binding = -216.21 +/- 0.97) and pyriproxyfen (a well-known larvicidal, Delta G binding= -435.95 +/- 2.06 kJ/mol). Considering future in vivo assays, we elaborated the theoretical synthetic route and made predictions of the synthetic accessibility (SA) (SwissADME), lipophilicity and water solubility (SwissADME) of the promising compounds identified in the present study. Our in silico results show that MP-416 and MP-073 molecules could be potent insecticides against the Aedes aegypti mosquitoes.Pro-Reitoria de Pesquisa e Pos-Graduacao (PROPESP) of Federal University of Para via the Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute, Federal University of Para PROPESP/UFPA-Edital 02/2022-PAPQ/PROPES

    Bioanalysis of Small Molecule Pharmaceuticals: Simultaneous Determination in Biological Fluid Samples from Multiple Species by the Management of Matrix Effects

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    A strategy is described for method evaluation to manage the influence of endogenous compounds to induce bias in pharmaceutical quantification from blood samples of different animal species resulting from ionisation matrix effects. The approach introduces the possibility of simultaneous cross animal species calibration for ethical reasons using a simple indicative test, which also rapidly demonstrates the utility of a test assay in other matrices. A quantitative Turboflow LC-MS/MS assay was evaluated using samples prepared in species matched controlled matrices with deuterated internal standardisation. The method was subsequently tested to assess the analysis of samples from multiple animal species using calibration samples from a single matrix origin. The object of this was to enable the substitution of analytical control samples in rodent plasma, reducing the plasma volume required, therefore the number of rodents used indirectly to support development studies. The method was unsuccessful due to concentration bias in identically prepared test samples. The bias origin was investigated using a fixed ratio solution of the analyte and its deuterated analogue with matrix test aliquots. The investigation identified non equivalent relative ionisation efficiency between compounds. The ratio method is proposed as an evaluation strategy for matrix effects causing non-equivalent response ratios. The origin of this deviation was identified using a post column standard infusion test highlighting a region of ionisation suppression co-eluting with the analyte. Full scan acquisition analysis revealed co-elution of endogenous glycerophospholipids. The relative expression of these compounds between species was investigated, employing a precursor ion scanning method of a common product ion indicative of phosphotidyl choline compounds; the human diversity was also investigated. Distribution was found to differ between animal species, which was further tested by construction of a model using partial least squares regression which correctly identified the species origin of all non-primate species tested. The mechanism of differentiation between compound and deuterated analogue by endogenous phosphotidyl choline was proposed as micellar phase equilibrium following elution from the HPLC column. A new Turboflow LC-MS/MS assay was optimised with attention to the resolution of glycerophospholipid interferences and retested for applicability between species. It was simultaneously applied to the analysis of small volume whole blood samples via dried blood spots on filter paper. Precision and bias were acceptable for the analysis of rat and mouse samples using human control plasma. Analysis of incurred ex-vivo samples from rats was successful in demonstrating equivalence between calibration sources

    Investigating the chemical space and metabolic bioactivation of natural products and cross-reactivity of chemical inhibitors in CYP450 phenotyping

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    Includes bibliographical references.Natural products have been exploited by humans as the most consistently reliable source of medicines for hundreds of years. Owing to the great diversity in chemical scaffolds they encompass, these compounds provide an almost limitless starting point for the discovery and development of novel semi-synthetic or wholly synthetic drugs. In Africa, and many other parts of the world, natural products in the form of herbal remedies are still used as primary therapeutic interventions by populations far removed from conventional healthcare facilities. However, unlike conventional drugs that typically undergo extensive safety studies during development, traditional remedies are often not subjected to similar evaluation and could therefore harbour unforeseen risks alongside their established efficacy. A comparison of the ‘drug-like properties’ of 335 natural products from medicinal plants reported in the African Herbal Pharmacopoeia with those of 608 compounds from the British Pharmacopoeia 2009 was performed using in silico tools. The data obtained showed that the natural products differed significantly from conventional drugs with regard to molecular weight, rotatable bonds and H-bond donor distributions but not with regard to lipophilicity (cLogP) and H-bond acceptor distributions. In general, the natural products were found to exhibit a higher degree of deviation from Lipinski’s ‘Rule-of-Five’. Additionally, these compounds possessed a slightly greater number of structural alerts per molecule compared to conventional drugs, suggesting a higher likelihood of undergoing metabolic bioactivation

    Ocular and systemic pharmacokinetic models for drug discovery and development

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    Drug discovery and development is a long process: it takes usually 12 to 15 years before a drug candidate reaches the market. The pharmacokinetics of the drug is an important aspect of drug discovery and development, because the drug must reach its target site and exert the therapeutic response. The pharmacokinetic parameters of new compounds should be investigated early in drug discovery. Pharmacokinetic predictions can be made with Quantitative Structure-Property Relationships (QSPR) which are computational models that correlate chemical features with pharmacokinetic properties. The correlations are based on in vivo or in vitro pharmacokinetic data and molecular descriptors. QSPR models can be used to predict the pharmacokinetic parameters even before any actual drug synthesis and can be exploited to guide drug discovery. Pharmacokinetic models can also simulate concentration profiles of drugs during the drug discovery and development process. It was decided to develop QSPR models of pharmacokinetic parameters of drugs to be delivered by the systemic or ocular routes. A combination of Principal Component Analysis and Partial Least Square multivariate statistical methods was used to obtain QSPR equations for volume of drug distribution and fraction of unbound drug in plasma. Parallel modelling of these parameters resulted in acceptable R2 (0.58 - 0.77) and Q2 values (0.55 - 0.58). These models are based on a large set of structurally unrelated compounds, they are open and they have a defined applicability domain. Charge and lipophilicity related descriptors were the relevant ones which influenced the volume of distribution and free fraction of drug in plasma. Pharmacokinetics is an important factor in the development of ocular medications, because the ocular drug targets are difficult to reach, particularly in the posterior tissues such as retina and choroid. Therefore, drugs need to be injected intravitreally in the treatment of retina and choroid diseases (e.g. in exudative age-related macular degeneration) and thus prediction of intravitreal pharmacokinetics would be especially advantageous in ocular drug discovery and development. The first comprehensive collection of intravitreal volume of distribution and clearance values of compounds was collated based on extensive rabbit eye data from the literature. Moreover, predictive QSPR models for intravitreal clearance and half-life were created which had R2 and Q2 values of 0.62 0.84 for clearance and 0.61 - 0.80 for half-life. LogD7.4 and hydrogen bonding capacity defined the intravitreal clearance and half-life of compounds with a molecular weight below 1500 Da. The intravitreal volumes of drug distribution lay within a narrow range (80% within 1.18 - 2.28 ml). The QSPR models for intravitreal clearance and the typical values for intravitreal volumes of distribution were implemented in pharmacokinetic simulation models; the simulated profiles based on the real and predicted pharmacokinetic parameter values were similar. Thus, a combination of QSPR and pharmacokinetic models can be used in drug discovery and development to aid in the design of drugs and drug delivery systems. A comprehensive comparison of intravitreal pharmacokinetic data between rabbit and human was carried out to clarify the translational value of the rabbit model. The analysis revealed that the rabbit can be considered as a clinically predictive animal model for intravitreal pharmacokinetics of small molecules (18 Da - 1500 Da) and macromolecules (7.1 kDa - 149 kDa). There was a correlation between the intravitreal clearance values in human patients and healthy rabbits; they showed similar, but not identical, absolute values. The intravitreal pharmacokinetics of small molecules is mainly governed by permeability-limited clearance across blood-ocular barriers and occurs via the posterior route, whereas large molecules are cleared mostly via the anterior route. Although the literature contains some claims about the significance of the viscosity of the vitreous, it seems that this is not a major factor in drug elimination from the eye. In conclusion, new in silico tools were generated for systemic and ocular pharmacokinetics and drug delivery. These models can be exploited in industrial drug discovery and will hopefully speed up the development of new medications.Silmätaudeissa lääkehoitoa vaikeuttaa se, että lääkehoitoa on vaikea saattaa perille silmänpohjaan verkkokalvon soluihin, joissa näkövammaisuuteen ja sokeutumiseen johtavat muutokset tavallisesti tapahtuvat. Näin ollen lääkkeitä joudutaan antamaan silmän sisään toistuvina injektioina esimerkiksi verkkokalvon ikärappeuman hoidossa. Lääkkeiden kulkeutumisen ymmärtäminen ja ennustaminen tietokoneella auttaa pitkävaikutteisten injektioiden ja vaihtoehtoisten lääkkeen antotapojen kehittämistä. Väitöskirjassa kehitettiin tällaisia tietokonemalleja pohjautuen julkaistuihin tutkimuksiin

    Bioanalysis of small molecule pharmaceuticals : simultaneous determination in biological fluid samples from multiple species by the management of matrix effects

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    A strategy is described for method evaluation to manage the influence of endogenous compounds to induce bias in pharmaceutical quantification from blood samples of different animal species resulting from ionisation matrix effects. The approach introduces the possibility of simultaneous cross animal species calibration for ethical reasons using a simple indicative test, which also rapidly demonstrates the utility of a test assay in other matrices. A quantitative Turboflow LC-MS/MS assay was evaluated using samples prepared in species matched controlled matrices with deuterated internal standardisation. The method was subsequently tested to assess the analysis of samples from multiple animal species using calibration samples from a single matrix origin. The object of this was to enable the substitution of analytical control samples in rodent plasma, reducing the plasma volume required, therefore the number of rodents used indirectly to support development studies. The method was unsuccessful due to concentration bias in identically prepared test samples. The bias origin was investigated using a fixed ratio solution of the analyte and its deuterated analogue with matrix test aliquots. The investigation identified non equivalent relative ionisation efficiency between compounds. The ratio method is proposed as an evaluation strategy for matrix effects causing non-equivalent response ratios. The origin of this deviation was identified using a post column standard infusion test highlighting a region of ionisation suppression co-eluting with the analyte. Full scan acquisition analysis revealed co-elution of endogenous glycerophospholipids. The relative expression of these compounds between species was investigated, employing a precursor ion scanning method of a common product ion indicative of phosphotidyl choline compounds; the human diversity was also investigated. Distribution was found to differ between animal species, which was further tested by construction of a model using partial least squares regression which correctly identified the species origin of all non-primate species tested. The mechanism of differentiation between compound and deuterated analogue by endogenous phosphotidyl choline was proposed as micellar phase equilibrium following elution from the HPLC column. A new Turboflow LC-MS/MS assay was optimised with attention to the resolution of glycerophospholipid interferences and retested for applicability between species. It was simultaneously applied to the analysis of small volume whole blood samples via dried blood spots on filter paper. Precision and bias were acceptable for the analysis of rat and mouse samples using human control plasma. Analysis of incurred ex-vivo samples from rats was successful in demonstrating equivalence between calibration sources.EThOS - Electronic Theses Online ServiceSanofi-AventisGBUnited Kingdo
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