Research Interests biomolecular modeling, computer-aided drug design, drug development, force field development, structure activity relationships

Investigating the impact of ribosome modification on the binding of antibiotics using Grand Canonical Monte Carlo- Molecular Dynamics

Bacterial resistance to antibiotics is a serious public health problem that requires the continuous development of new antibiotics. Bacteria acquire resistance to macrolide antibiotics by (1) effluxing the drug from the cell, (2) modifying the drug, or (3) modifying the drug target (i.e., the 50S subunit of the ribosome) to abrogate or completely abolish binding. While newer antibiotics are able to avoid the first two mechanisms, they remain unable to overcome resistance due to ribosomal modification, particularly due to methyltransferase (i.e., erm) enzymes. We have applied computer-aided drug design methods designed explicitly for studies of the ribosome to better understand the relationship between modification of the ribosome by erms and the binding of telithromycin, a 3rd generation ketolide antibiotic derived from erythromycin. While we confirm that ribosomal modification leads to decreased binding due to disruption of key interactions with the drug, we find these modifications effect a structural rearrangement of the entire region of the ribosome responsible for binding macrolide antibiotics. This information will be useful in the design of novel antibiotics that are effective against resistant bacteria possessing modified ribosomes.

Article:[PLoS Computational Biology]

Conformationally sampled pharmacophore of desmethyl macrolides

CSP is a pharmacophore-based method in which ensembles of ligand conformations are generated using MD simulations from which probability distributions are calculated for select distances and angles in the molecule (i.e. pharmacophore features).(Bernard, Coop, and MacKerell 2003) Analyses are then performed to correlate biological activity of the ligand with the CSP pharmacophoric features. The method may be used qualitatively to identify biologically important geometric features as well as quantitatively to predict the activity of other ligands. Notably, physical properties of ligands may be readily incorporated into CSP models. We have applied CSP to analogs of the antibiotic telithromycin to show that removal of methyl groups from the antibiotic ring reduced activity compared to telithromycin by increasing the conformational flexibility of the analog, which results from the decrease in hydrophobic VDW contacts as methyls are removed.

Article:[ACS Med Chem Let]

Force field development-additive and polarizable models

Force field-based simulations are an important part of in silico drug design. A force field is the potential energy function and the collection of parameters that have been optimized for use in that potential energy function. The usefulness of a force field in drug design is based on the availability of quality parameters for the target biomolecule and the ligands under study. Hence, force field optimization is crucial to ensure accuracy of computer simulations. Much effort has been made in the MacKerell lab to develop and refine the CHARMM force fields that are used extensively in biomolecular simulations, including the additive suite of force fields for all types of biomolecules as well as the Drude polarizable force field that accounts for polarization explicitly. If you would like to know more about these efforts, please contact us!