Dataset Information

The relationship between target-class and the physicochemical properties of antibacterial drugs.

ABSTRACT: The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower logP and higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e., composed of a complex of RNA and protein) fall outside the conventional human 'drug-like' chemical space; whereas antibacterials that modulate bacterial protein targets, generally comply with the 'rule-of-five' guidelines for classical oral human drugs. Our analysis suggests a strong target-class association for antibacterials-either protein-targeted or riboprotein-targeted. There is much discussion in the literature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our analysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery.

SUBMITTER: Mugumbate G

PROVIDER: S-EPMC4537081 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

The relationship between target-class and the physicochemical properties of antibacterial drugs.

Mugumbate Grace G Overington John P JP

Bioorganic & medicinal chemistry 20150428 16

The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower logP and higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins ...[more]

PMID: 25975639

Similar Datasets

Project description:This study shows the importance of the chosen method for assessing the glass-forming ability (GFA) and glass stability (GS) of a drug compound. Traditionally, GFA and GS are established using in situ melt-quenching in a differential scanning calorimeter. In this study, we included 26 structurally diverse glass-forming drugs (i) to compare the GFA class when the model drugs were produced by spray-drying with that when melt-quenching was used, (ii) to investigate the long-term physical stability of the resulting amorphous solids, and (iii) to investigate the relationship between physicochemical properties and the GFA of spray-dried solids and their long-term physical stability. The spray-dried solids were exposed to dry (<5% RH) and humid (75% RH) conditions for six months at 25 °C. The crystallization of the spray-dried solids under these conditions was monitored using a combination of solid-state characterization techniques including differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. The GFA/GS class assignment for 85% of the model compounds was method-dependent, with significant differences between spray-drying and melt-quenching methods. The long-term physical stability under dry condition of the compounds was predictable from GFA/GS classification and glass transition and crystallization temperatures. However, the stability upon storage at 75% RH could not be predicted from the same data. There was no strong correlation between the physicochemical properties explored and the GFA class or long-term physical stability. However, there was a slight tendency for compounds with a relatively larger molecular weight, higher glass transition temperature, higher crystallization temperature, higher melting point and higher reduced glass transition temperature to have better GFA and better physical stability. In contrast, a high heat of fusion and entropy of fusion seemed to have a negative impact on the GFA and physical stability of our dataset.

Project description:Owing to the peculiar broad-spectrum antimicrobial activities of zinc oxide nanoparticles (ZnO NPs), we envisaged their use to treat bacterial/mycobacterial/fungal infections during peritoneal dialysis (PD) of end-stage renal failure patients. However, a recent study from our lab showed that ZnO-NPs cannot be employed for the same in their naked form owing to their rapid agglomeration. Also, the naked ZnO-NPs showed strong interaction with organic acids present in the PD fluid (i.e., lactate and citrate present abundantly in almost all biological fluids) resulting in the formation of bioconjugates. Here, we propose that the surface coating of ZnO NPs may inhibit the binding interactions of NPs with the constituents of PD fluid. Therefore, in this study, we have carried out the surface coating of ZnO NPs with polyethylene glycol (PEG) of different molecular weights, followed by the investigations of physicochemical properties of PEGylated ZnO NPs dispersed in PD fluid using nuclear magnetic resonance (NMR) spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy. The interaction of PEGylated ZnO NPs has also been studied separately in glucose and lactic acid which are the main constituents of PD fluid and in citric acid. Although the X-ray diffraction and TEM results infer the colloidal stability of PEGylated ZnO NPs in PD fluid, FT-IR, UV-vis, and nuclear magnetic resonance results revealed the binding interactions of PEGylated ZnO NPs with the PD constituents. PEGylated ZnO NPs also interact strongly with the lactic acid and citric acid, leading to agglomeration, as observed previously for uncoated ZnO NPs. Further, the antibacterial activities of bare and PEG-coated ZnO NPs dispersion in PD fluid have been studied. A reduction in the bacterial inhibition effect against Staphylococcus aureus and Escherichia coli was observed for both the bare and PEG-coated ZnO NPs dispersed in PD fluid, indicating that the complex nature of PD fluid counteract on the efficiency of these nanobiotics.

Dataset Information

The relationship between target-class and the physicochemical properties of antibacterial drugs.

Publications

The relationship between target-class and the physicochemical properties of antibacterial drugs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure