We combine x-ray crystallography, cryo-EM and pharmacological assays to better understand how serotonin, therapeutics such as antipsychotics, and illicit drugs such as LSD stabilize different receptor conformations that cause different physiological effects. We further perform structure based drug design to computationally screen large compound libraries against our structures and identify and engineer novel compounds that serve as starting points for the development of better therapeutics.
Crystal Structure of a LSD-Bound Serotonin Receptor (Wacker et al., 2017)
GPCRs are targeted by about 35% of all available therapeutics that include antihistamines such as loratadine (Claritin), analgesics such as oxycodone (OxyContin), or antipsychotics such as aripiprazole (Abilify). GPCRs also mediate the effects of the most widely consumed psychoactive stimulant caffeine, or that of illicit substances such as LSD, heroin, or cannabis.
Our goal is a comprehensive mechanistic understanding of GPCR function using a combination of x-ray crystallography, cryo-EM, biochemical, and pharmacological assays. We are mainly interested in understanding how GPCRs are activated, inhibited, and how their activity can be modulated. This will serve as a basis to develop novel GPCR drugs that activate therapeutic signaling pathways while avoiding potentially pathological pathways.
Colas et al., 2016
Neurotransmitter Transporters are mainly responsible for storing neurotransmitters in intracellular vesicles, or clearing neurotransmitters from the synaptic cleft after neurotransmission. Antidepressants such as Fluoxetine (Prozac), stimulants such as amphetamines (Adderall), as well as illicit drugs such as methamphetamine (“crystal meth”) or cocaine act through this class of transporters.
We are mainly interested in understanding cargo recognition and transport mechanisms, as well as drug-mediated modulation of cargo transport. We use a combination of x-ray crystallography, ligand binding, and transport assays to elucidate these mechanisms and inform drug discovery at these important drug targets.
In collaboration with computational and medicinal chemistry groups here at Mount Sinai, we are trying to leverage mechanistic insights from our structural and molecular studies to generate novel tool compounds targeting both GPCRs and Transporters. We predominantly focus on the discovery of novel lead compounds from large computational screening campaigns, that are then rapidly improved and customized towards desired pharmacology using medicinal chemistry.
These studies are geared towards uncovering novel biology of selected drug targets in vitro and in vivo, and may even serve as a starting point towards the generation of novel therapeutics.
