Albocycline, a 14-membered macrolide, has gained recent attention as a new scaffoldfor the development of antibiotic inhibitors of MRSA (methicillin-resistant Staphylococcus aureus). Towards the goal of computationally designing analogs of albocycline, we have employed QM/MM methods to accurately predict the solution structure of albocycline and its O-desmethyl analog cineromycin B. REMD simulation using the GAFF forcefield was employed for initial conformational sampling, with subsequent QM refinement of conformational basins using DFT methods (B3LYP 6-311+g(2d,p)). Our results show a remarkable agreement between the QM predictions and experimental structural measurements (x-ray, NMR), and suggest the need for more accurate MD force fields to predict structures of such macrocycles. The high-quality QM models of albocycline we obtain are used to prioritize candidate analogs to synthesize, by predicting  whether proposed chemical modifications preserve the core macrolide structure. Further applications of these models include the generation of favorable poses for computational binding studies, as well as large-scale molecular simulations of ligand binding performed using the Folding@home distributed computing platform, with putative Mur enzyme targets in S. Aureus. Experimental validation of these predictions will come from total synthesis efforts, co-crystallization and photo affinity labeling studies.

Toward computational design of albocycline analogs

248th National Meeting (2014)

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