Evaluation of molecular target of ademol by chemoinformatic method

Background. Glutamate excitotoxicity and intracranial hypertension are potential targets for possible developments of pathogenetic therapy of brain lesions, in particular those associated with high intracranial pressure. The purpose of the work: using chemoinformatic methods to justify the intravenous use of ademol, to detect the ability of ademol to block β-adrenergic receptors, as well as to assess the possibility of its passage through the blood-brain barrier in terms of drug-likeness and bioavailability criteria. Materials and methods. All calculations of molecular descriptors were made using the software package SIB Swiss Institute of Bioinformatics, computing platform and Molinspiration Cheminformatics v2016.09, available online. Results. The molecular weight of ademol does not exceed 500, the average lipophilicity value calculated using software package is in the acceptable range for the above compounds. For ademol, the value of LogP is 2,736, which is higher than that of rimantadine (2,456), but lower than that of propranolol (2,967). The total polar surface area is calculated based on the methodology developed by Ertl et al. in the form of contributions of the sum of the planes of O- and N-atoms etc., as a part of the functional groups of polar fragments. To predict ademol pe-netration through the blood-brain barrier, descriptors calculated in silico were used — average lipophilicity, which appeared to be close to previously described lipophilicity coefficient in a mixture of octanol and phosphate buffer, and the total polar surface area of mo-lecules. Affinity correlation (LogKi, nM) with polarity for known β-blockers and ademol is described as a second-degree parabolic polynomial function. Conclusions. A model of affinity correlation with lipophilicity for a number of β-blockers was created and the affinity of ademol is predicted, which is close to that of high-affi-nity non-selective β-blockers.

Time scale of glycation in collagen of bovine pericardium-derived bio-tissues

Glycosylation is the process of combining one or more glucose molecules (or other monosaccharides) with molecules of a different nature (which are therefore glycosylated). In biochemistry, glycosylation is catalyzed by several specific enzymes, and assumes considerable importance since it occurs mainly at the expense of proteins and phospholipids which are thus transformed into glycoproteins and glycolipids. Conversely, in diabetes and aging, glycation of proteins is a phenomenon of non-enzymatic nature and thus not easily controlled. Glycation of collagen distorts its structure, renders the extracellular matrix stiff and brittle and at the same time lowers the degradation susceptibility thereby preventing renewal. Based on models detailed in this paper and with parameters determined from experimental data, we describe the glycation of type 1 collagen in bovine pericardium derived bio-tissues, upon incubation in glucose and ribose. With arginine and lysine/hydroxylysine amino acids as the primary sites of glycation and assuming that the topological polar surface area of the sugar molecules determines the glycation rates, we modelled the glycation as a function of time and determined the glycation rate and thus the progression of glycation as well as the resulting volume increase.

RP-18 TLC Chromatographic and Computational Study of Skin Permeability of Steroids

The skin permeability of steroids, as investigated in this study, is important because some of these compounds are, or could, be used in preparations applied topically. Several models of skin permeability, involving thin layer chromatographic and calculated descriptors, were generated and validated using Kp reference values obtained in silico and then tested on a group of solutes whose experimental Kp values could be found (log Kpexp). The study established that the most applicable log Kp model is based on RP-18 thin layer chromatographic data (RM) and the calculated descriptors VM (molar volume) and PSA (polar surface area). Two less efficient, yet simple, equations based on PSA or VM combined with HD (H-donor count) can be used with caution for rapid, rough estimations of compounds’ skin permeability prior to their chemical synthesis.

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). This modality has emerged as an orthogonal approach to the use of small-molecule inhibitors for knocking down classic targets and disease-related proteins classified, until now, as “undruggable.” In early 2019, the first targeted protein degraders reached the clinic, drawing attention to PROTACs as one of the most appealing technology in the drug discovery landscape. Despite these promising results, PROTACs are often affected by poor cellular permeability due to their high molecular weight (MW) and large exposed polar surface area (PSA). Herein, we report a comprehensive record of PROTAC design, pharmacology and thermodynamic challenges and solutions, as well as some of the available strategies to enhance cellular uptake, including suggestions of promising biological tools for the in vitro evaluation of PROTACs permeability toward successful protein degradation.

In-vitro Anti-trypanosomal and Cytotoxicity Evaluation of 3-methyl-3-4-dihydroquinazolin-2(1H)-one Derivatives

Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093–45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14 having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM Graphical Abstract.

O USO DE SOFTWARES LIVRES EM AULA PRÁTICA SOBRE FILTROS MOLECULARES DE BIODISPONIBILIDADE ORAL DE FÁRMACOS

THE USE OF FREE SOFTWARES IN PRACTICAL CLASS ABOUT THE MOLECULAR FILTERS OF ORAL BIOAVAILABILITY OF DRUGS. The study of the physical chemical properties to predict the oral bioavailability of drugs is a widely tool used by researches on the Pharmaceutical and Medicinal Chemistry field. Even though it is a deeply studied subject, it is a complex task to teach to pharmacy students. Lipinski stablished that molecular weight, lipophilicity, hydrogen bond donors and acceptors are of great importance for oral bioavailability. In addition, Veber and Lovering added other properties, such as number of rotatable bonds, fraction of sp3 hybridized carbon and polar surface area that amplified the Lipinski Rule of 5. In this sense, the access to chemical databases and the comprehension of this information is an important task to undergraduate and graduate students. Thus, this work aims a new teaching methodology that values the critical interpretation of data and that favors the students comprehension beyond stablished rules.

In Vitro Antioxidant and Anti-Glycation Activity of Resveratrol and Its Novel Triester with Trolox

Resveratrol (RSV) is well known for its many beneficial activities, but its unfavorable physicochemical properties impair its effectiveness after systemic and topical administration; thus, several strategies have been investigated to improve RSV efficacy. With this aim, in this work, we synthesized a novel RSV triester with trolox, an analogue of vitamin E with strong antioxidant activity. The new RSV derivative (RSVTR) was assayed in vitro to evaluate its antioxidant and anti-glycation activity compared to RSV. RSVTR chemical stability was assessed at pH 2.0, 6.8, and 7.2 and different storage temperatures (5 °C, 22 °C, and 37 °C). An influence of pH stronger than that of temperature on RSVTR half-life values was pointed out, and RSVTR greatest stability was observed at pH 7.2 and 5 °C. RSVTR showed a lower antioxidant ability compared to RSV (determined by the oxygen radical absorbance capacity assay) while its anti-glycation activity (evaluated using the Maillard reaction) was significantly greater than that of RSV. The improved ability to inhibit the glycation process was attributed to a better interaction of RSVTR with albumin owing to its increased topological polar surface area value and H-bond acceptor number compared to RSV. Therefore, RSVTR could be regarded as a promising anti-glycation agent worthy of further investigations.

PREDICTION ANALYSIS OF PHARMACOKINETIC PARAMETERS OF SEVERAL ORAL SYSTEMIC DRUGS USING INSILICO METHOD

Objective: This research aims to observe the pharmacokinetic parameters that can be predicted using a software, discover the best software to predictpharmacokinetic properties, and analyze the correlation between pharmacokinetic parameters used as descriptors with absorption percentage(%ABS) from references.Methods: This research was conducted using Molinspiration, QikProp, admetSAR, SwissADME, Chemicalize, and pkCSM software. This researchanalyzed 34 oral systemic drug compounds for absorption rate and six descriptors comprising molecular weight (MW), logP, hydrogen bond acceptor(HBA), hydrogen bond donor (HBD), polar surface area (PSA), and pKa.Results: SwissADME showed the most accurate prediction of MW, logP, and HBD. Chemicalize showed the most accurate prediction of HBA, PSA, andpKa. Further, admetSAR showed the most accurate prediction of Caco-2 permeability. The highest R value was obtained from the correlation between%ABS with Caco-2 permeability on 34 drug compounds (R=0.8211).Conclusion: The highest R value was obtained from the correlation between %ABS with Caco2 permeability on 34 drug compounds (R=0.8211),which showed a significant relationship (*p<0.001). This indicates that oral systemic drugs are affected by Caco-2 permeability. Moreover, the result of this research can be considered for the development of oral systemic drugs.

Computerassisted models for Blood Brain Barrier permeation of 1, 5-Benzodiazepines

Aim: To generate and validate predictive models for blood brain permeation (BBB) of CNS molecules using QSPR approach. Background: Prediction of molecules crossing BBB remain a challenge in drug delivery. Predictive models are designed for evaluation of set of preclinical drugs which may serve as alternatives for determining BBB permeation by experimentation. Objective: The objective of present study was to generate QSPR models for permeation of CNS molecules across BBB and its validation using existing in-house leads. Method: The present study envisaged the determination of set of molecular descriptors which are considered significant correlative factors for BBB permeation property. Quantitative Structure Property Relationship (QSPR) approach was followed to describe the correlation between identified descriptors for 45 molecules and highest, moderate and least BBB permeation data. The molecular descriptors were selected based on drug likeness, hydrophilicity, hydrophobicity, polar surface area, etc. of molecules which served highest correlation with BBB permeation. The experimental data in terms of logBB were collected from available literature, subjected for 2D-QSPR model generation using regression analysis method like Multiple Linear Regression (MLR). Result: The best QSPR model (Model 3) exhibited regression coefficient as R2= 0.89, F = 36; Q2= 0.7805 and properties such as polar surface area, hydrophobic hydrophilic distance, electronegativity etc., which were considered key parameters in determination of the BBB permeability. The developed QSPR models were validated with in-house 1,5-benzodiazepines molecules and correlation studies were conducted between experimental and predicted BBB permeability. Conclusion: The QSPR model 3showed predictive results in good agreements with experimental results for blood brain permeation. Thus, this model was found to be satisfactory in achieving goodcorrelation between selected descriptors and BBB permeation for benzodiazepines and tricyclic compounds.