Molecular similarity of MDR inhibitors

Everyone is free to re-use the published material if proper accreditation/citation of the original publication is given. http://creativecommons.org/licences/by/3.0/The molecular similarity of multidrug resistance (MDR) inhibitors was evaluated using the point centred atom charge approach in an attempt to find some common features of structurally unrelated inhibitors. A series of inhibitors of bacterial MDR were studied and there is a high similarity between these in terms of their shape, presence and orientation of aromatic ring moieties. A comparison of the lipophilic properties of these molecules has also been conducted suggesting that this factor is important in MDR inhibition.Peer reviewe

In silico structural evaluation of short cationic antimicrobial peptides

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Cationic peptides with antimicrobial properties are ubiquitous in nature and have been studied for many years in an attempt to design novel antibiotics. However, very few molecules are used in the clinic so far, sometimes due to their complexity but, mostly, as a consequence of the unfavorable pharmacokinetic profile associated with peptides. The aim of this work is to investigate cationic peptides in order to identify common structural features which could be useful for the design of small peptides or peptido-mimetics with improved drug-like properties and activity against Gram negative bacteria. Two sets of cationic peptides (AMPs) with known antimicrobial activity have been investigated. The first reference set comprised molecules with experimentally-known conformations available in the protein databank (PDB), and the second one was composed of short peptides active against Gram negative bacteria but with no significant structural information available. The predicted structures of the peptides from the first set were in excellent agreement with those experimentally-observed, which allowed analysis of the structural features of the second group using computationally-derived conformations. The peptide conformations, either experimentally available or predicted, were clustered in an “all vs. all” fashion and the most populated clusters were then analyzed. It was confirmed that these peptides tend to assume an amphipathic conformation regardless of the environment. It was also observed that positively-charged amino acid residues can often be found next to aromatic residues. Finally, a protocol was evaluated for the investigation of the behavior of short cationic peptides in the presence of a membrane-like environment such as dodecylphosphocholine (DPC) micelles. The results presented herein introduce a promising approach to inform the design of novel short peptides with a potential antimicrobial activity.Peer reviewedFinal Published versio

NMR spectroscopy in drug discovery and development: Evaluation of physico-chemical properties

Determination of physico-chemical properties of compounds is one of the corner-stones in selection of hit molecules for further progression into lead development in the modern drug discovery process. The speed of traditional analyses and limited quantities of hit molecules are obstacles for efficient acquisition of experimental data. Herein, the range of applications of quantitative nuclear magnetic resonance (NMR) spectroscopy as a fast technique used to evaluate solubility, log P and pKa are discussed

3D-QSAR студија аналога аденозин 5'-фосфосулфата (APS) као лиганда за APS редуктазу

Metabolism of sulfur (sulfur assimilation pathway, SAP) is one of the key pathways for the pathogenesis and survival of persistant bacteria, such as Mycobacterium tuberculosis (Mtb), in the latent period. Adenosine 5'-phosphosulfate reductase (APSR) is an important enzyme involved in the SAP, absent from the human body, so it might represent a valid target for development of new antituberculosis drugs. This work aimed to develop 3D-QSAR model based on the crystal structure of APSR from Pseudomonas aeruginosa, which shows high degree of homology with APSR from Mtb, in complex with its substrate, adenosine 5'-phosphosulfate (APS). 3D-QSAR model was built from a set of 16 nucleotide analogues of APS using alignment-independent descriptors derived from molecular interaction fields (MIF). The model improves the understanding of the key characteristics of molecules necessary for the interaction with target, and enables the rational design of novel small molecule inhibitors of Mtb APSR.Метаболизам сумпора (пут асимилације сумпора, SAP) један је од кључних путева за патогенезу и преживљавање Mycobacterium tuberculosis (Mtb) у латентном периоду. Аденозин 5'-фосфосфат редуктаза (APSR) је значајан ензим који је укључен у SAP, не налази се у људском организму и може бити валиднo циљно место за развој нових анти- туберкулотика. Циљ овог рада је развој 3D-QSAR модела који се заснива на кристалној структури APSR из Pseudomonas aeruginosa, који има висок степен хомологије са APSR из Mtb, у комплексу са супстратом, аденозин 5'-фосфoсулфатом (APS). 3D-QSAR модел је постављен коришћењем сета 16 нуклеотидних аналога APS применом дескриптора неза- висних од полазних тачака, изведених из поља молекуларних интеракција (MIF). Модел служи за боље разумевање кључних карактеристика молекула неопходних за интерак- цију са циљним местом, у сврху рационалног дизајнирања малих молекула, инхибитора APSR из Mtb

A phytochemical comparison of saw palmetto products using gas chromatography and (1) H nuclear magnetic resonance spectroscopy metabolomic profiling

© 2014 The Authors. Journal of Pharmacy and Pharmacology published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly citedPreparations containing saw palmetto berries are used in the treatment of benign prostatic hyperplasia (BPH). There are many products on the market, and relatively little is known about their chemical variability and specifically the composition and quality of different saw palmetto products notwithstanding that in 2000, an international consultation paper from the major urological associations from the five continents on treatments for BPH demanded further research on this topic. Here, we compare two analytical approaches and characterise 57 different saw palmetto products.Peer reviewedFinal Published versio

Evaluation of Encapsulation Potential of Selected Star-Hyperbranched Polyglycidol Architectures: Predictive Molecular Dynamics Simulations and Experimental Validation

Polymers, including non-linear copolymers, have great potential in the development of drug delivery systems with many advantages, but the design requires optimizing polymer–drug interactions. Molecular dynamics (MD) simulations can provide insights into polymer–drug interactions for designing delivery systems, but mimicking formulation processes such as drying is often not included in in silico studies. This study demonstrates an MD approach to model drying of systems comprising either hydrophilic tinidazole or hydrophobic clotrimazole drugs with amphiphilic hyperbranched copolyethers. The simulated drying protocol was critical for elucidating drug encapsulation and binding mechanisms. Experimentally, two polymers were synthesized and shown to encapsulate clotrimazole with up to 83% efficiency, guided by interactions with the hydrophobic core observed in simulations. In contrast, tinidazole is associated with surface regions, indicating capacity differences between drug types. Overall, this work highlights MD simulation of the drying process as an important tool for predicting drug–polymer complex behaviour. The modelled formulation protocol enabled high encapsulation efficiency and opened possibilities for the design of delivery systems based on computationally derived binding mechanisms. This demonstrates a computational–experimental approach where simulated drying was integral to elucidating interactions and developing optimized complexes, emphasizing the value of molecular modelling for the development of drug delivery formulations

The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Elucidation of molecular mechanisms of activity of Echinacea spp. constituents for possible treatment of COVID 19 by computer-aided methods

Echinacea spp. have long history of use, dating from American natives. Among ten, three species (Echinacea purpurea (L.), Echinacea pallida (Nutt.) and Echinacea angustifolia (DC.)), are the most used, alone or in mixes, for treatment of various conditions, such are infections, cancers etc. Recently, it was shown that Echinacea spp. are effective in treatment of COVID 19, inhibiting progress of SARS CoV2 development. Due to availability of structures of certain number of chemical constituents of Echinacea spp. and 3D structures of possible targets included in processes of interaction, elucidation of its molecular mechanisms of action was performed by computational methods. Three approaches for evaluation of molecular mechanisms of Echinacea spp. constituents (24 from Echinacea purpurea and 10 from other Echinacea spp.) for possible treatment of recent COVID 19 pandemia are presented. First, docking studies of Echinacea spp. constituents (34) were performed on three targets, according to literature as the most important for SARS CoV2 virus spread and development: SARS CoV2 spike protein and angiotensin converting enzyme (ACE2) receptor responsible for virus entry, as well as SARS-CoV-2 metalloproteinase Mpro as the most responsible in mediation of viral transcription and replication. Second, physicochemical properties and pharmacokinetic-related characterization (Lipinksi Rule of five) of Echinacea spp. constituents in conformation with minimum energy, were performed by Data Warrior program. Results show that 4/34 compounds have negative values of log P (hydrophilic), 6/34 showed negative results regarding selection by Rule of five, among which 5 significantly differ in H-bonding capacity, which indicates different properties for oral absorption and distribution within the organism, as well as mode of action. Drug likeness, calculated for fragments of 34 constituents, is scattered within 15 units of difference. Third, the probability of interaction of Echinacea spp. constituents with targets was estimated by use of SwissTarget Prediction program, based on query molecule showing activity on certain class of targets. Results showed that cannabinoid receptors (CNR) 1 and 2 (17 and 16 units) and peroxisome proliferatoractivated receptor gamma (PPARγ) (15 units) are the most preferable targets for interactions. Possible molecular mechanisms involved in evidented pharmacological records in treatment of COVID 19 by Ehinacea spp. were elucidated with regard of results of all three methods.10th IAPC Meeting, Book of Abstract