Ligand-Receptor Interactions and Machine Learning in GCGR and GLP-1R Drug Discovery.

The large amount of data that has been collected so far for G protein-coupled receptors requires machine learning (ML) approaches to fully exploit its potential. Our previous ML model based on gradient boosting used for prediction of drug affinity and selectivity for a receptor subtype was compared with explicit information on ligand-receptor interactions from induced-fit docking. Both methods have proved their usefulness in drug response predictions.

Virtual Screening of Constituents for the Identification of Selective Ligands for Cannabinoid Receptor 2.

The selective targeting of the cannabinoid receptor 2 (CB2) is crucial for the development of peripheral system-acting cannabinoid analgesics. This work aimed at computer-assisted identification of prospective CB2-selective compounds among the constituents of . The molecular structures and corresponding binding affinities to CB1 and CB2 receptors were collected from ChEMBL.

Computer-Aided Discovery of New Solubility-Enhancing Drug Delivery System.

The poor aqueous solubility of active pharmaceutical ingredients (APIs) places a limit on their therapeutic potential. Cyclodextrins (CDs) have been shown to improve the solubility of APIs, but the magnitude of the improvement depends on the structure of both the CDs and APIs. We have developed quantitative structure-property relationship (QSPR) models that predict the stability of the complexes formed by a popular poorly soluble antibiotic, cefuroxime axetil (CA) and different CDs.

Computer-Aided Design of Cefuroxime Axetil/Cyclodextrin System with Enhanced Solubility and Antimicrobial Activity.

This study aimed to investigate changes in the solubility and antimicrobial efficacy of cefuroxime axetil (CA) when incorporated into cyclodextrin (CD). While choosing the CD, the validated in silico model was used. A theoretical model based on docking and molecular mechanics/generalized born surface area was validated using a curated dataset of API (active pharmaceutical ingredient)-CD stability constants.

The Radiation Sterilization of Ertapenem Sodium in the Solid State.

For the first time, the influence of ionising radiation on the physicochemical properties of ertapenem in solid state was studied. During our studies, we evaluated the possibility of applying radiosterilization to obtain sterile ertapenem. Spectroscopic (Fourier Transform Infrared (FT-IR)), thermal (differential scanning calorimetry (DSC), chromatography (High-Performance Liquid Chromatography (HPLC) and HPLC-MS), and X-ray powder diffraction (XRPD) studies shown that irradiation of ertapenem with the 25 kGy, the dose required to achieve sterility, does not change the physicochemical properties of the studied compound.

Machine Learning Approach for Determining the Formation of β-Lactam Antibiotic Complexes with Cyclodextrins Using Multispectral Analysis.

The problem of determining the formation of complexes of β-lactam antibiotics with cyclodextrins (CDs) and the interactions involved in this process were addressed by machine learning on multispectral images. Complexes of β-lactam antibiotics, including cefuroxime axetil, cefetamet pivoxil, and pivampicillin, as well as CDs, including αCD, βCD, γCD, hydroxypropyl-αCD, methyl-βCD, hydroxypropyl-βCD, and hydroxypropyl-γCD, were prepared in all combinations. Thermograms confirming the formation of cyclodextrin complexes were obtained using differential scanning calorimetry.

Supramolecular Complexes of Graphene Oxide with Porphyrins: An Interplay between Electronic and Magnetic Properties.

Graphene oxide (GO) was modified by two modified porphyrins (THPP and TCPP) to form GO⁻porphyrin hybrids. Spectroscopic measurements demonstrated the formation of stable supramolecular aggregates when mixing two components in solution. The Fourier transform infrared (FTIR) and Raman scattering measurements confirm π-stacking between hydrophobic regions of GO nanoflakes and porphyrin molecules.

Cyclodextrins as multifunctional excipients: Influence of inclusion into β-cyclodextrin on physicochemical and biological properties of tebipenem pivoxil.

A novel approach for drug design based on the oral carbapenem analog tebipenem pivoxil (TP) has been proposed. The formation of the tebipenem pivoxil-β-cyclodextrin (TP-β-CD) complex resulted in changes concerning physicochemical properties of TP, which is significant for planning the development of an innovative pharmaceutical formulation as well as in the modifications of biological activity profile of the studied delivery system. The inclusion of TP into β-cyclodextrin (β-CD) was confirmed by spectral (infrared and Raman spectroscopies) and thermal method (differential scanning calorimetry).

Enhanced pharmacological efficacy of sumatriptan due to modification of its physicochemical properties by inclusion in selected cyclodextrins.

The study focused on the pharmacological action of sumatriptan, in particular its antiallodynic and antihyperalgesic properties, as an effect of cyclodextrinic inclusion of sumatriptan, resulting in changes of its physicochemical qualities such as dissolution and permeability through artificial biological membranes, which had previously been examined in vitro in a gastro-intestinal model. The inclusion of sumatriptan into β-cyclodextrin and 2-hydroxylpropylo-β-cyclodextrin by kneading was confirmed with the use of spectral (fourier-transform infrared spectroscopy (FT-IR); solid state nuclear magnetic resonance spectroscopy with magic angle spinning condition, H and C MAS NMR) and thermal (differential scanning calorimetry (DSC)) methods. A precise indication of the domains of sumatriptan responsible for its interaction with cyclodextrin cavities was possible due to a theoretical approach to the analysis of experimental spectra.

Effects of inclusion of cetirizine hydrochloride in β-cyclodextrin.

Following the preparation of inclusion complex of cetirizine (CTZ) and β-cyclodextrin (β-CD), the compound was investigated to assess the possibility of modifying the physicochemical properties (solubility, release, stability, permeability) of CTZ after complexation that are vital for subsequent formulation studies involving the said complex. Changes in FT-IR/Raman spectra, DSC thermograms and XRD diffractograms confirmed the formation of a CTZ-β-CD system. Hydrophilic interaction chromatography with a DAD detector was employed to determine alterations of the CTZ concentration during studies following complexation.

Comprehensive spectral identification of key intermediates to the final product of the chiral pool synthesis of radezolid.

Radezolid (RAD, 12), biaryl oxazolidinone, was synthesised with small modifications according to the methods described in the literature. The pharmacological activity is observed only for (S)-enantiomer, therefore its synthesis is oriented towards obtaining a single isomer of required purity and desired optical configuration. The intermediate products of RAD synthesis were characterised using H- and C-NMR, as well as the 2D correlation HSQC and HMBC (2, 5, 9, 10), furthermore studied using infrared radiation (FT-IR), Raman scattering (3, 5, 9), and electronic circular dichroism (ECD) (5, 12) spectroscopy.

Application of spectroscopic methods (FT-IR, Raman, ECD and NMR) in studies of identification and optical purity of radezolid.

In the presented study, N-{[(5S)-3-(2-fluoro-4'-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (radezolid) was synthesized and characterized using FT-IR, Raman, ECD and NMR. The aim of this work was to assess the possibility of applying classical spectral methods such as FT-IR, Raman, ECD and NMR spectroscopy for studies on the identification and optical purity of radezolid. The experimental interpretation of FT-IR and Raman spectra of radezolid was conducted in combination with theoretical studies.

Quantitative structure-retention relationship model for the determination of naratriptan hydrochloride and its impurities based on artificial neural networks coupled with genetic algorithm.

Mathematical modeling of Quantitative Structure - Property Relationships met great interest in fields of in silico drug design and more recently, pharmaceutical analysis. In our approach we proposed automated method of creation Quantitative Structure-Retention Relationship (QSRR) for analysis of triptans, selective serotonin 5-HT receptor agonists used for the treatment of acute headache. The method was created using hybrid machine learning approach, namely Genetic algorithm (GA) coupled with artificial neutral networks (ANN).

STUDIES OF THE CRYSTALLINE FORM OF CEFUROXIME AXETIL: IMPLICATIONS FOR ITS COMPATIBILITY WITH EXCIPIENTS.

Amorphous and crystalline forms of cefuroxime axetil were identified and characterized using DSC, XRPD, SEM, FT-IR and Raman spectroscopy. Based on the results of chromatographic studies, changes in the kinetic mechanism and rate of degradation of the crystalline form of cefuroxime axetil in binary systems with excipients were also evaluated. The findings suggest that the mechanism of degradation of cefuroxime axetil in such systems depends on two factors: the applied excipient and storage conditions.

β-Cyclodextrin complexation as an effective drug delivery system for meropenem.

Following the preparation of an inclusion complex of β-cyclodextrin and meropenem, methods based on FT-IR, Raman and DSC were used for its characterization. An analysis of changes in the stability of meropenem after complexation showed that the complex may serve as a valuable delivery system significantly contributing to enhanced meropenem stability in aqueous solutions and in the solid phase. Due to a sustained transfer of meropenem from the cavity of the cyclodextrin it was possible to maintain a constant desired meropenem concentration over a period of 20 h, as confirmed by a release study.

Solid-state stability studies of crystal form of tebipenem.

The aim of this study was to determine the kinetic and thermodynamic parameters of tebipenem degradation in the solid state. The process was analyzed based on the results obtained by a high performance liquid chromatography (HPLC) method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopic (RS) studies. In dry air, the degradation of tebipenem was a first-order reaction depending on the substrate concentration while at an increased relative air humidity tebipenem was degraded according to the kinetic model of autocatalysis.

Complex of rutin with β-cyclodextrin as potential delivery system.

This study aimed to obtain and characterize an RU-β-CD complex in the context of investigating the possibility of changes in the solubility, stability, antioxidative and microbiological activity as well as permeability of complexated rutin as against its free form. The formation of the RU-β-CD complex via a co-grinding technique was confirmed by using DSC, SEM, FT-IR and Raman spectroscopy, and its geometry was assessed through molecular modeling. It was found that the stability and solubility of the so-obtained complex were greater compared to the free form; however, a slight decrease was observed inits antibacterial potency.

Prediction of HPLC retention times of tebipenem pivoxyl and its degradation products in solid state by applying adaptive artificial neural network with recursive features elimination.

A sensitive and fast HPLC method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS) was developed for the determination of tebipenem pivoxyl and in the presence of degradation products formed during thermolysis. The chromatographic separations were performed on stationary phases produced in core-shell technology with particle diameter of 5.0 µm.

Application of spectroscopic methods for identification (FT-IR, Raman spectroscopy) and determination (UV, EPR) of quercetin-3-O-rutinoside. Experimental and DFT based approach.

Vibrational (FT-IR, Raman) and electronic (UV, EPR) spectral measurements were performed for an analysis of rutin (quercetin-3-O-rutinoside) obtained from Rutaofficinalis. The identification of rutin was done with the use of FT-IR and Raman spectra. Those experimental spectra were determined with the support of theoretical calculations based on a DFT method with the B3LYP hybrid functional and 6-31G(d,p) basis set.

An Approach to Transfer Methods from HPLC to UHPLC Techniques in Some Carbapenems.

Stability-indicating LC methods were developed and validated for the quantitative determination of doripenem, meropenem and tebipenem in the presence of their degradation products formed during forced degradation studies. Isocratic HPLC and UHPLC separations were performed with a core-shell Kinetex 1.7, 2.

Computational study of influence of diffuse basis functions on geometry optimization and spectroscopic properties of losartan potassium.

The work was aimed at investigating the influence of diffusion of basis functions on the geometry optimization of molecule of losartan in acidic and salt form. Spectroscopic properties of losartan potassium were also calculated and compared with experiment. Density functional theory method with various basis sets: 6-31G(d,p) and its diffused variations 6-31G(d,p)+ and 6-31G(d,p)++ was used.

Tebipenem pivoxyl. Derivative spectroscopy study of stability of the first oral carbapenem.

A simple and selective derivative spectrophotometric method was developed for the quantitative determination of tebipenem and its pivoxyl ester in the presence of degradation products formed during degradation in aqueous solutions (hydrolysis, oxidation, phosphate buffer pH ∼6.0) and in the solid state (photolysis, thermolysis in dry air and at an increased relative air humidity). The method was based on zero-crossing first-derivative spectrophotometry (λ=341 nm for tebipenem pivoxyl and λ=320 nm for tebipenem), which eliminated the overlapping caused by various degradation products.