Computational Modeling of Gpcrs: Towards Understanding Receptor Signaling for Biology and Drug Discovery
Computational Modeling of GPCRs: Towards Understanding Receptor Signaling for Biology and Drug Discovery Vsevolod (Seva) Katritch JCIMPT-ComplexesBarcelona, | January Jul 13 7,th 2011, 2018 1 GPCRs in Human Biology & Pharmacology Nat Rev Drug Disc 5:993 (2006) >30% of all drugs GPCR targets GPCR Targets: >120 established > 800 potential 800 GPCR are receptors for: Disorders Targeted Clinically Neurotransmitters ( adrenaline, dopamine, Psychiatric, Learning & Memory, histamine, acetylcholine, adenosine, Mood, Sleep, Drug Addiction, Stress, serotonin, glutamate, anandamide, GABA) Anxiety, Pain, Social Behavior… Hormones & Neuropeptides (opioid, neurotensin, glucagon, CRF, Cardiovascular, Endocrine, Obesity, galanin, orexin, oxytocin, neuromedin, Immune, HIV, Reproductive … melanocortins, somatostatin, ghrelin, TRH, TSH, GnRH, , PTH, THS, LH… >30 total ) Neurodegenerative and Autoimmune Disease … Immune system (chemokine, sphingosine 1 phosphate) Brain Development, Regenerative Med. Development (Frizzled, Adhesion) Sensory Cancer Light, Taste, Olfactory (388) GPCR Structure and Function Thousands of Ligands - Chemical Diversity >800 Different Human Receptors (largest family in human genome) Share 7TM Fold But Diverse We use structure Structural and modeling Features to learn: • Molecular Recognition • Signaling Mechanisms and to design: Dozens of Effectors New tool compounds GPCR New receptor properties Consortium Katritch et al 2013 Annu Rev Pharm. Tox. 53, 531-556 Stevens et al. 2013, Nat Rev Drug Discov, 12: 25–34 Outline ➢Rational prediction of stabilizing mutations: CompoMug ➢New insights into GPCR function and allosteric mechanisms ➢Structure-Based ligand discovery for GPCRs 5 Why Stabilizing GPCRs? ➢ Crystallography: ➢ Synergistic with fusions and truncations ➢ Reduces heterogeneity ➢ Allows stabilization of active or inactive states ➢ Allows co-crystallization with low-affinity ligands ➢ Biophysical characterization ➢ SPR ➢ NMR ➢ Drug discovery ➢ More robust assays for HTS Navratilova et al.
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