Despite sustained efforts, a detailed understanding of the relation between structural properties of abused substances and their complex physiological and behavioral phenotypes, is still lacking. Psychotropic drugs often target neuronal membrane proteins that are functionally activated through complicated allosteric mechanisms. Through such mechanisms, structurally similar ligands can induce a large diversity of biochemical and biophysical responses on common protein targets. For example, ligands that bind the same GPCR can modulate very different signaling pathways and downstream cellular phenotypes; this is known as functional selectivity and has been observed for hallucinogenic drugs of abuse at the 5-HT2A serotonin receptor and for various antipsychotics at D2 dopamine receptors. Another class of synaptic signaling targets, the neurotransmitter:sodium symporters, are also targeted by psychostimulants and antidepressants, and each substrate induces very different gating and transport dynamics. Recent breakthroughs in biophysical experimentation (crystallography, single molecule FRET) and computational methodology (large scale molecular dynamics simulations and methods for energy calculations) are yielding detailed molecular information about the structures and dynamics of these molecular targets and complexes with drugs of abuse. Combined, these results indicate that the diversity of functional responses induced by different drugs targeting the same receptor (or transporter) is the direct result of ligand-specific allosteric modulation of the proteins, preparing them for differential coupling and interactions in the signaling cascade. On this basis, I propose to develop, implement, and apply to the targets of drugs of abuse studied in my laboratory (the 5-HT2A and D2 receptors, and the LeuT-like neurotranmitter transporters including DAT and SERT) a series of novel computational methods that can analyze rigorously the ligand-determined responses of the drug targets. The novel tools and approaches will be applied to achieve a new perspective and understanding of drug-target interactions, functional selectivity, and the mechanism of action of many important antipsychotics and drugs of abuse. I will develop these techniques with an emphasis on structure-function relationships so that results can be expressed in a manner that allows experimental probing, e.g., with mutagenesis, pharmacological profiling, and the application of structural techniques such as single molecule FRET. I will produce new experimentally testable hypotheses and work with experimental collaborators in the design of new types of experiments aimed at expanding the understanding the mechanisms of such drugs and medications.
Drugs of abuse in many families (hallucinogens like LSD, and psychostimulants like cocaine and amphetamine) produce dramatic responses from their targets in the brain, although these targets are shared by normal neurotransmitters like serotonin and dopamine; current understanding of drug mechanisms cannot explain this phenomenon. The proposed study will develop and implement novel computational tools to find ligand-specific changes produced in drug targets by the interaction of drugs of abuse. This work will focus on and synaptic G protein-coupled receptors and transporters, and should ultimately provide a new framework by which we can understand the mechanism and phenotypic properties of psychotropic drugs of abuse, paving the way for new understanding and the design of therapeutics.
