PT  - JOURNAL ARTICLE
AU  - Anita K. Nivedha
AU  - Christofer S. Tautermann
AU  - Supriyo Bhattacharya
AU  - Sangbae Lee
AU  - Paola Casarosa
AU  - Ines Kollak
AU  - Tobias Kiechle
AU  - Nagarajan Vaidehi
TI  - Identifying Functional Hotspot Residues for Biased Ligand Design in G-Protein-Coupled Receptors
AID  - 10.1124/mol.117.110395
DP  - 2018 Apr 01
TA  - Molecular Pharmacology
PG  - 288--296
VI  - 93
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/93/4/288.short
4100  - http://molpharm.aspetjournals.org/content/93/4/288.full
SO  - Mol Pharmacol2018 Apr 01; 93
AB  - G-protein-coupled receptors (GPCRs) mediate multiple signaling pathways in the cell, depending on the agonist that activates the receptor and multiple cellular factors. Agonists that show higher potency to specific signaling pathways over others are known as “biased agonists” and have been shown to have better therapeutic index. Although biased agonists are desirable, their design poses several challenges to date. The number of assays to identify biased agonists seems expensive and tedious. Therefore, computational methods that can reliably calculate the possible bias of various ligands ahead of experiments and provide guidance, will be both cost and time effective. In this work, using the mechanism of allosteric communication from the extracellular region to the intracellular transducer protein coupling region in GPCRs, we have developed a computational method to calculate ligand bias ahead of experiments. We have validated the method for several β-arrestin–biased agonists in β2-adrenergic receptor (β2AR), serotonin receptors 5-HT1B and 5-HT2B and for G-protein–biased agonists in the κ-opioid receptor. Using this computational method, we also performed a blind prediction followed by experimental testing and showed that the agonist carmoterol is β-arrestin–biased in β2AR. Additionally, we have identified amino acid residues in the biased agonist binding site in both β2AR and κ-opioid receptors that are involved in potentiating the ligand bias. We call these residues functional hotspots, and they can be used to derive pharmacophores to design biased agonists in GPCRs.