Thursday 6th June, 2013
11:00am to 11:30am
Lead optimization, evolving a hit compound into a potential drug molecule, requires insight, experience, data, application and a good portion of luck. Correctly modeling protein-ligand interactions is difficult at the current state of the art, so making correct predictions of which alterations to make to a molecule to achieve a given goal (potency, selectivity, modulating off-target effects) is uncertain. Based on the idea that water is an excellent ligand for a protein and that highly potent ligands must make all the interactions that water does with a protein binding site, we have developed a tool, SZMAP, to model water energetics in a binding site. Uniquely in this area SZMAP uses a semi-continuum approach to calculating water thermodynamics, combining the speed and power of continuum solvent methods with the discrete nature of explicit solvent methods. In lead optimization, SZMAP can guide ligand design decisions by identifying waters that increase or decrease binding affinity, rapidly highlighting where small ligand modifications could mimic water interactions and geometry better, and suggesting where a substituent could displace neighboring waters that are hindering binding. The speed of SZMAP and its ability to focus on synthetically accessible modifications to a ligand allows it to have significant impact on chemistry decisions in lead optimization programs, reducing cycle time and increasing the rate at which project goals can be met.
11:30am SDOVS: A Solvent Dipole Ordering-Based Method for Virtual Screening by Naoya Nagata
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