New crystal structures G-protein coupled receptors and transporters create new opportunities for focused structure based discovery of chemical modulators with improved properties, as well as building models for natural peptide or protein modulators. The pipeline consists of the following steps: (i) building models of subtypes and missing or different loops, (ii) validating and guiding models with known chemical information about active compounds, (iii) screening for new binders including allosteric modulators. This docking and scoring part of the procedure is complicated by geometrical inaccuracies of the binding pocket and deficiencies of the scoring function which includes electrostatic desolvation. We demonstrate that using additional fields to guide the docking process helps to improve the results. Parts of the procedure is illustrated on Dopamine, adenosine A1 receptors and serotonin transporter.

Improving the binding models of small molecules, proteins, and peptides to GPCRs and transporters

248th National Meeting (2014)

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