title: Physicochemical profile of macrolides and their comparison with small molecules.
abstract: 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 α(1)-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.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. stepanic@irb.hr
authors.forename: Višnja
authors.initials: V
authors.lastname: Stepanić
authors.forename: Dinko
authors.initials: D
authors.lastname: Ziher
authors.forename: Vesna
authors.initials: V
authors.lastname: Gabelica-Marković
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.forename: Shenaz
authors.initials: S
authors.lastname: Nunhuck
authors.forename: Klara
authors.initials: K
authors.lastname: Valko
authors.forename: Sanja
authors.initials: S
authors.lastname: Koštrun
mesh_terms: D055598:Chemical Phenomena; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism*; D009961:Orosomucoid / Q000378:metabolism; D010539:Permeability; D012709:Serum Albumin / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility
chemical_list: D018942:Macrolides; D009961:Orosomucoid; D012709:Serum Albumin; D054852:Small Molecule Libraries; D004121:Dimethyl Sulfoxide