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izvor podataka: crosbi

Physicochemical profile of macrolides and their comparison with small molecules (CROSBI ID 180494)

Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija

Stepanić, Višnja ; Žiher, Dinko ; Gabelica-Marković, Vesna ; Jelić, Dubravko ; Nunhuck, Shenaz ; Valko, Klara ; Koštrun, Sanja Physicochemical profile of macrolides and their comparison with small molecules // European journal of medicinal chemistry, 47 (2012), 462-472. doi: 10.1016/j.ejmech.2011.11.016

Podaci o odgovornosti

Stepanić, Višnja ; Žiher, Dinko ; Gabelica-Marković, Vesna ; Jelić, Dubravko ; Nunhuck, Shenaz ; Valko, Klara ; Koštrun, Sanja

engleski

Physicochemical profile of macrolides and their comparison with small molecules

Macrolides are stereospecific macrolactones of high molecular weights. Herein, 600 mostly semisynthetic macrolides are compared with 50, 000 small non-macrolide synthetic molecules in terms of measured physicochemical properties in order to assess the drug-likeness and developability chances of macrolides. The pre-selected set of diverse macrolides is comprised mostly of derivatives of clarithromycin and azithromycin cores. Lipophilicity (CHI logD), affinity for immobilized artificial membranes (CHI IAM), human serum albumin (HSA) and α1-acid glycoprotein (AGP) plasma protein bindings (PPB), DMSO precipitative solubility as well as artificial membrane permeability (AMP) have been determined by high-throughput screening methods. It has been found that macrolides and small molecules have similar lipophilicity profiles, though macrolides show weaker PPB and have better solubility than small discovery molecules. However, macrolides are poorly permeable and have high affinity for immobilized artificial membranes signifying their strong interaction with biological phospholipids. In order to retain the drug-like profile, the design of novel macrolide molecules should be focused on optimisation of macrolide cores, that is macrolactone moiety with sugars and other small substituents avoiding large substituents and flexible linkers such as in conjugate derivatives.

drug-likeness ; high-throughput screening ; lipopilicity ; macrolides ; physicochemical property

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Podaci o izdanju

47

2012.

462-472

objavljeno

0223-5234

1768-3254

10.1016/j.ejmech.2011.11.016

Povezanost rada

Kemija, Temeljne medicinske znanosti, Farmacija

Poveznice
Indeksiranost