Bio Balance is currently developing robust protocols for construction of 3D models of molecules. These strategies include: construction of 3D models of bioactive molecules with their electronic properties included. This capability impacts on both the design of bioactive agents and the assessment of their adverse effects because it allows explicit modeling of these agents with the proteins most relevant to their mechanism of action.
The increase in the affinity of agonists with increasing pH, together with experiments using thiol specific reagents, indicate that G protein coupled receptors contain an ionizable cysteine residue at the ligand binding site. Since treatments with reducing agents have produced functional activation and potentiated agonist stimulation, it is likely that the sulfhydryl influences ligand efficacy and receptor activation. Working together with Dr. Lester Rubenstein, at Mount Sinai's Department of Physiology and Biophysics, we have derived a two-state acid-base model and a corresponding molecular model in order to test the hypothesis that cysteine modulation of ligand binding is related to ligand efficacy. We show that pH-dependent binding is correlated with ligand efficacy at the 5HT2A receptor. In general, efficacy is determined by the preference of a ligand for the base over the acid form of the receptor. Efficacy is also described as a thermodynamic coupling free energy between a ligand and the acid and base states of the receptor. Molecular modeling of the third transmembrane domain containing a conserved cysteine residue shows that efficacy can be measured as the difference in the electrostatic interaction energies of a ligand with the acid and base forms of this receptor model. The cysteine residue provides the largest contribution to this electrostatic interaction energy difference, and thereby, ligand efficacy.
List of companies and individuals that have collaborated with Bio Balance:
¬ Gwathmey, Inc. - www.gwathmey.com/
¬ CEREP - http://www.cerep.fr/
¬ DSS Infotech International - http://www.dssinfotech.com/
¬ Dr. Peter Cherry, CCNY - http://med.cuny.edu/
¬ Dr. Lester Rubenstein, MSSM, Dept. of Physiology and Biophysics - http://www.mssm.edu/physbio/
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