A comparative assessment of octanol-water partitioning and distribution constant estimation methods for perfluoroalkyl carboxylates and sulfonates

New experimental data is available in the literature regarding the octanol-water distribution behavior of representative straight chain perfluoroalkyl carboxylate (PFCA) and sulfonate (PFSA) congeners. The current study provides the first investigation into the predictive ability of various software programs for estimating the corresponding octanol-water partitioning (log P) and distribution (log D) constants of PFCAs and PFSAs. Wide predictive variation was found within and between the various methods. Several programs were able to accurately estimate the log P/D fragmental contributions of a -CF~2~- group for PFCAs, as well as the associated Gibbs free energies for partitioning into octanol from water due to the hydrophobic character of the perfluoroalkyl chain (Δ~hydrophobic~G~ow~). Only the SPARC log D method accurately predicted the electrostatic contributions of the carboxylate head group (Δ~electrostatic~G~ow~) towards octanol-water partitioning for PFCAs. Similar log D values and organic carbon normalized sediment-water partitioning coefficients (K~oc~) for PFCAs and PFSAs having equivalent perfluoroalkyl chain lengths suggests potentially equivalent Δ~electrostatic~G~ow~ and Δ~hydrophobic~G~ow~ contributions towards lipophilic partitioning for these two contaminant classes, regardless of head group identity. In contrast, there are potentially different Δ~electrostatic~G~ow~ and Δ~hydrophobic~G~ow~ contributions towards proteinophilic partitioning

Quantitative Structure-Activity Relationship Study of Some Antipsychotics by Multiple Linear Regressions

The retention behavior and lipophilicity parameters of some antiphychotics were determined using reversed-phase thin layer chromatography. Quantitative structure-activity relationships studies have been performed to correlate the molecular characteristics of observed compounds with their retention as well as with their chromatographically determinated lipophilicity parameters. The effect of different organic modifiers (acetone, tetrahydrofuran, and methanol) has been studied. The retention of investigated compounds decreases linearly with increasing concentration of organic modifier. The chemical structures of the antipsychotics have been characterized by molecular descriptors which are calculated from the structure and related to chromatographically determinated lipophilicity parameters by multiple linear regression analysis. This approach gives us the possibility to gain insight into factors responsible for the retention as well as lipophilicity of the investigated set of the compounds. The most prominent factors affecting lipophilicity of the investigated substances are Solubility, Energy of the highest occupied molecular orbital, and Energy of the lowest unoccupied molecular orbital. The obtained models were used for interpretation of the lipophilicity of the investigated compounds. The prediction results are in good agreement with the experimental value. This study provides good information about pharmacologically important physico-chemical parameters of observed antipsychotics relevant to variations in molecular lipophilicity and chromatographic behavior. Established QSAR models could be helpful in design of novel multitarget antipsychotic compounds

Investigação in silico de compostos naturais com potencial inibitório da enzima conversora de angiotensina I em angiotensina II / In silico investigation of natural compounds with inhibitory potential of angiotensin I-converting enzyme I in angiotensin II

A hipertensão arterial é o principal fator de risco para doenças cerebrovasculares e doenças isquêmicas do coração, sendo uma das causas mais importante para a morbidade e a mortalidade cardiovascular. Devido às limitações e severos efeitos colaterais dos fármacos disponíveis no mercado empregados para hipertensão, torna-se necessário o desenvolvimento de novos fármacos, mais eficazes e com menos eventos adversos. Assim, o objetivo deste estudo foi avaliar, por meio de técnicas de modelagem molecular, a solubilidade em água e o coeficiente de partição de nove compostos naturais inibidores da enzima conversora de angiotensina, além de verificar os aspectos moléculas dessas interações. Foi observado que todos os compostos alvos do estudo possuem solubilidade adequada para interagir com barreiras biológicas hidrofóbicas e fluídos hidrofílicos. Foi observado também, que os compostos naturais interagiram de forma atrativa com os aminoácidos do sítio ativo da enzima e com o íon zinco, fator de extrema importância para uma boa inibição da enzima conversora de angiotensina. O presente estudo proporciona uma melhor compreensão da inibição da enzima conversora de angiotensina por compostos naturais, o que pode contribuir para o desenvolvimento de novos anti-hipertensivos. 

Липофильность BODIPY флуорофоров и их распределение в системе октанол-1–вода

The work covers synthesis and lipophilicity estimation of several BODIPY dyes. For these compounds, the distribution between 1-octanol and water layers is experimentally described and the corresponding partition coefficients LogP are calculated. The experimental LogP values are compared with popular fragment-based methods XLopP3, ALogPS, WLogP, SILICOS-IT and MLogP. Additionally, the hydrophobic and polar surface areas are found with quantum-mechanical calculations. That allowed to find a correlation between the LogP coefficient and the molecular surface topology, as well as to determine the corresponding incremental values of the methyl, acetyl, and phenyl substituents. Выполнен синтез нескольких BODIPY флуорофоров и рассмотрено их распределение в системе октанол-1–вода. Для оценки эффективности использования расчетных методов при описании липофильности BODIPY производных обсуждены такие подходы, как XLopP3, ALogPS, WLogP, SILICOS-IT и MLogP. С помощью квантово-механических расчетов найдены гидрофобная и полярная площади молекулярных поверхностей соединений. Это позволило установить корреляцию между коэффициентом LogP и топологией молекулярной поверхности, а также определить соответствующие величины инкрементов для метильного, ацетильного и фенильного заместителей

A few atoms make the difference: Synthetic, CD, NMR and computational studies on antiviral and antibacterial activities of glycopeptide antibiotic aglycon derivatives

K

Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection

The estimation of the accuracy of predictions is a critical problem in QSAR modeling. The "distance to model" can be defined as a metric that defines the similarity between the training set molecules and the test set compound for the given property in the context of a specific model. It could be expressed in many different ways, e.g., using Tanimoto coefficient, leverage, correlation in space of models, etc. In this paper we have used mixtures of Gaussian distributions as well as statistical tests to evaluate six types of distances to models with respect to their ability to discriminate compounds with small and large prediction errors. The analysis was performed for twelve QSAR models of aqueous toxicity against T. pyriformis obtained with different machine-learning methods and various types of descriptors. The distances to model based on standard deviation of predicted toxicity calculated from the ensemble of models afforded the best results. This distance also successfully discriminated molecules with low and large prediction errors for a mechanism-based model developed using log P and the Maximum Acceptor Superdelocalizability descriptors. Thus, the distance to model metric could also be used to augment mechanistic QSAR models by estimating their prediction errors. Moreover, the accuracy of prediction is mainly determined by the training set data distribution in the chemistry and activity spaces but not by QSAR approaches used to develop the models. We have shown that incorrect validation of a model may result in the wrong estimation of its performance and suggested how this problem could be circumvented. The toxicity of 3182 and 48774 molecules from the EPA High Production Volume (HPV) Challenge Program and EINECS (European chemical Substances Information System), respectively, was predicted, and the accuracy of prediction was estimated. The developed models are available online at http://www.qspr.org site

Development of new Nanoplatforms for the treatment and prevention of Atherosclerosis

openOver the last decade, many studies suggest that inflammation has an important role in atherosclerosis progression and development. In the last years, old cheaper drugs, Methotrexate (MTX) and Colchicine (COL) were considered to treat this pathology due to their anti-inflammatory effects. MTX, a conventional chemotherapeutic medicine currently representing the first-line option in inflammatory diseases like rheumatoid arthritis (RA) and psoriatic arthritis, was proposed in the clinical trial Cardiovascular Inflammation Reduction Trial (CIRT). Even though many studies have demonstrated this drug's beneficial activity on animals/patients with atherosclerosis, the clinical trial failed. Col is known for its therapeutic use in gout and Familial Mediterranean Fever (FMF). In these patients, it was noticed a reduction of myocardial infarctions after the use of Colchicine. Its effect is associated with a stronger effect in the inhibition of inflammasome activation and IL-1β secretion. These observations are at the base of different clinical trials like Low-Dose Colchicine (LoDoCo), A second Low Dose Colchicine (LoDoCo2), Low Dose Colchicine after Myocardial Infarction (LoDoCo-MI). In general, their clinical use is limited by their several side effects and, furthermore, in MTX’s case is even more difficult due to its poor bioavailability and solubility in biological fluids. Taking this into account, nanomedicine might become a valid ally in furnishing potent tools to ease combined treatment and increase drug accumulation at the target site. Thus, this work aims to propone nanoparticles, polymeric, and lipid to improve the stability and solubility of encapsulated cargos, promote transport across membranes, and prolong circulation times to increase safety and efficacy. Here, it was proposed two different strategies for modifying the methotrexate by conjugating the DSPE and PEG. The prodrugs obtained (DSPE-MTX and PEG-MTX) were used to synthesize liposomes, including one or both of them. Physiochemical features were tested. The DSPE-MTX was selected (due to the instability at pH 6.8 of the system) and delivered by liposomes (MTX-LIP) and spherical polymeric nanoparticles (MTX-SPNs). Both nanoparticle formulations presented similar features. For the lipidic nanoparticles, the size is 174±2 nm (PdI: 0.15 ± 0.0007), and Zeta Pot -48 ± 0.02 mV; for the polymeric nanocarriers, the size is 208±2 nm (PdI: 0.15 ± 0.02), and Zeta Pot 45.8 ± 0.02 mV. MTX encapsulation efficiency (EE%) 70±5% for Lip-MTX and 1.5±0.2% for SPNs-MTX. Foam cells were obtained by treating rat bone marrow-derived monocytes (BMDM) with oxLDL. The treatment with the two nanoformulations was able to reverse foam cells maturation into macrophages. Both MTX-LIP and MTX-SPNs decreased cholesterol amounts after 24 hours in BMDM. The efficacy of the treatment was also proved by gene expression analysis. RT-PCR showed that the CD36 and SRA-1 gene expression (regulating oxLDL influx) was minimal. The reverse cholesterol transporter (ABCA1) in foam cells treated with the nanoformulations was inducing a 2-fold compare the CTRL. MTX-LIP and MTX-SPNs also reduced inflammatory gene expression (IL-6, IL-1β, and TNFα). MTX-LIP was used in vivo in a murine model of atherosclerosis. ApoE-/- mice, fed with a high-fat diet for 28 days, were treated for 4 weeks (once every three days) with MTX-LIP. Plaque burden was measured, revealing a reduction in plaque area for the treated mice. These results influenced a new line of thinking; it could be possible to boost the liposomes' anti-inflammatory effect combining in the same particles the MTX and the Colchicine (Col). Particles have a size around 100 nm with stability upon 4 days. The liposomes' encapsulation efficiency was ~ 28 % for MTX and ~ 33 % for COL with a ratio of 1:16. The anti-inflammatory effect was tested on the primary cell line (BMDM). Specifically, liposomes with MTX and Col were able to reduce the inflammation caused by the LPS. At the same time, they were able to modulate the foam cell marker (ABCA1), reflecting a reduction of the expression of IL-1β by 3-fold, IL-6 by 2-fold, and moderately of TNF-α. These results would suggest that combining the chemotherapeutic drugs in the liposomes could strongly reduce the inflammation modulating the disease progression. These data suggest that MTX and COL loaded nanoparticles could be the new strategy for the treatment of atherosclerosis.openXXXIII CICLO - BIOINGEGNERIA E ROBOTICA - BIOENGINEERING AND ROBOTICSDecuzzi, PaoloDI FRANCESCO, Valentin

The In Vitro Pharmacological Evaluation of Tetrahydrocannabivarin (THCV) For Intestinal Inflammatory Conditions

The recreational and medicinal use of Cannabis for certain human pathologies has received tremendous attention in recent years. Numerous pre-clinical and clinical findings on the benefits of cannabinoids, the naturally occurring constituents in Cannabis, against epilepsy, neuropathic pain, and gastrointestinal (GI) syndromes have allowed many governmental and research sectors to further investigate their therapeutic potential and adverse effects. Currently, several extensively researched cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) have shown to possess therapeutic and pharmacological effects in aiding the treatment of various medical conditions. However, due to a desire to enhance our increasing understanding of the physiochemical and pharmacokinetic (PK) characteristics of THC and CBD, research on certain cannabinoids such as tetrahydrocannabivarin (THCV) has not always been the primary focus. Studies on THCV indicated anti-inflammatory effects in in vitro cell lines and in vivo animal models which compelled us to assess the PK characteristics of THCV. In addition to its PK characteristics, our aim was to evaluate the effects of THCV on how it may affect inflammatory conditions of the GI tract such as inflammatory bowel disease (IBD). We first investigated THCV’s intestinal permeation profile and directly assessed its effects on intestinal barrier integrity with an in vitro Transwell system coupled with human epithelial derived cell line comprised of colorectal adenocarcinoma cells (Caco-2). We then examined its interaction with different plasma proteins in human plasma through its relative bound fraction and the unbound fraction in the blood (fu(b)) by adopting the 3-solvent extraction plasma protein binding technique. Enzyme kinetic analysis was conducted to better understand the contribution of liver to the first-pass metabolism and systemic clearance of THCV using human liver microsomes (HLM). Its in vitro intrinsic clearance (Clint,u) was calculated using the substrate depletion approach and was ranked as to whether it was a low, intermediate or high clearance drug. As a secondary aim, we established a 3-D intestinal organoid (IO) model derived from human inducible pluripotent stem cells (iPSCs) for the preliminary screening of THCV putative anti-inflammatory effects. Collectively, THCV demonstrated limited permeation in the Transwell system with a high degree of non-specific binding to plasticware, relatively higher unbound fraction (fu(b)) compared to the literature, and classified as a high clearance drug indicated by its Clint,u value. Further, THCV showed promising anti-inflammatory effects by upregulating an anti-inflammatory cytokine in the IO system. These studies revealed key PK parameters of THCV that is currently unavailable in the literature while the new IO system was capable of upregulating key pro-inflammatory responses upon lipopolysaccharide (LPS) stimulation, which may bridge the gap between traditional in vitro cell culture and in vivo animal models