Specific Formulations to Prevent Receptor Desensitization
Bio Balance is positioned for strategic alliances or cooperative research and development agreements with pharmaceutical or biotechnology companies to develop therapeutic compositions. Instead of designing new molecules, this technology produces enhanced compositions for superior therapeutic end-points. These compositions are designed by combining an agonist with an antagonist in an optimal ratio. These "Optimal Ratio Combinations" (ORCs) have the potential to save the expense and time associated with screening for a therapeutic candidate molecule, in which 1 out of 10,000 explored molecules becomes a drug. The time to market could be substantially reduced because the component molecules in these compositions are well known and characterized. These compositions have the potential to save the pharmaceutical industry millions of dollars per drug. The expertise Bio Balance brings to these endeavors is the determination of the ORCs as well as a general, biophysical description for modeling the receptor response.

Molecular Modeling
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.

Construction of 3-Dimensional (3D) Models of Proteins
Bio Balance is currently developing protocols for construction of 3D models of proteins. These strategies include: construction of 3D models of globular proteins from templates by homology modeling.

Computer Modeling of Drug-Receptor Interactions
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.