research

research

Current Research

I am interested in the use of virtual screening to discover new chemical leads for unmet medical needs.

Homology modelling in virtual screening

G-protein coupled receptors (GPCRs), are the largest superfamily of proteins in the human body, and represent >30% of all marketed therapeutics. Since 2007, only a handful of GPCR structures have been determined. An attractive method to fill in the gaps for structure-based drug prediction is homolgy modeling, however, it is critical that models be accurate enough to reliably support structure-based drug discovery. We investigate the applicability of modeling GPCR for prospective computational drug discovery.

Protein flexibility in virtual screening

Movement is crucial to protein-ligand interactions, yet experimentally determined crystallographic structures of proteins can give us only a static snapshot. I aim to develop methods for virtual screen that will allow protein target flexibility. I use multi-conformational docking screens to discover a broad range of novel chemotypes and binding conformations relevant to the activation of the beta-2-adrenergic receptor.

Previous interests

Protein Dynamics

Protein dynamics that are important to biological function often happen on a time scale that is unattainable through detailed computational simulation methods as they often involve crossing high-energy barriers. We developed new coarse-grained computational techniques to study the transitions between the static experimentally determined structures of proteins and to predict features of the biologically relevant intermediate conformations. We have also suggested an objective test to evaluate competing methods and used it to look at popular online coarse-grained trajectory servers. Given how often experimentalists are now using such coarse-grained interpolation methods (often via web servers) to infer functionally relevant motion, an objective test, as well as a better performing method, is needed.

Weiss DR, Levitt M (2009), Can Morphing Methods Predict Intermediate Structures?, J Mol Biol 385: 665-674

Analysis of the simulated behavior of fullerenes in water

We use molecular dynamics simulation to look at the water structure surrounding a single molecule of Buckminsterfullerene (C₆₀), and to learn about the diffusive behavior of the solute. We compare this behavior to that of a small, spherically symmetrical hydrophobic solute, namely methane.

Weiss DR, Raschke TM, Levitt M (2008), How Hydrophobic Buckminsterfullerene Affects Surrounding Water Structure, J Chem Phys B 112(10):2981-90.