Three-Dimensional QSAR Analysis and Design of New 1,2,4-Oxadiazole Antibiotics

ERIKA J. LEEMANS; KIRAN V. MAHASENAN; MALIKA KUMARASIRI; EDWARD SPINK; DERONG DING; PETER I. O'DANIEL; MARC A. BOUDREAU; ELENA LASHTOCHKIN; SEBASTIAN A. TESTERO; TAKAO YAMAGUCHI; MIJOON LEE; DUSAN HESEK; JED F. FISHER; MAYLAND CHANG; SHAHRIAR MOBASHERY

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2016 vol. 26 p. 1011 - 1015

0960-894X

The oxadiazole antibiotics, a class of newly discoveredcompounds that are active against Gram-positive bacteria, target bacterialcell-wall biosynthesis by inhibition of a family of essential enzymes, thepenicillin-binding proteins. Ligand-based 3D-QSAR analyses by ComparativeMolecular Field Analysis (CoMFA), Comparative Molecular Shape Indices Analysis(CoMSIA) and Field-Based 3D-QSAR evaluated a series of 102 members of thisclass. This series included inactive compounds as well as compounds that weremoderately to strongly antibacterial against Staphylococcus aureus. Multiplemodels were constructed using different types of energy minimization and chargecalculations. The CoMFA model carrying MMFF94 charges gave good statistical resultsfor the training set, verified by a high cross-validated q2 value of 0.70 and anon-validated r2 value of 0.85, and therefore holding robustness. Validationwith an external test set gave a predictive ability with an r2pred value of0.77. CoMFA derived contour maps successfully defined favored and disfavoredregions of the molecules in terms of steric and electrostatic properties forsubstitution.