This is an application for competitive renewal of a Research Scientist Award (K05). The research program is theoretical and centers on the computational modeling and simulation of ligand/receptor interactions of hallucinogens and structurally cognate non-hallucinogenic compounds. Three dimensional molecular models of 5-HT receptors on which hallucinogenic molecules act will be constructed and used to learn the molecular determinants for the recognition of such compounds by the serotonin receptor subtypes. Structure-function relations of the receptors will be explored computationally to understand the structure- activity relations of the ligands. The computational simulation of intramolecular signal transduction related to ligand binding to the receptor models will be used to learn the determinants for hallucinogenic activity. The working hypothesis is that the hallucinogenic potential of certain compounds reflects specific differences relative to congeneric nonhallucinogens. that are identifiable from the molecular mechanisms of ligand/receptor interaction and from the structural and dynamic response of the receptors to these interactions. This hypothesis leads to the proposed investigations of the molecular detaIls of the discriminant factors responsible for the special properties underlying the actions of hallucinogenic drugs of abuse. The theoretical research program is aligned with an interactive Research Project Grant (IRPG) aimed at understanding the mechanisms of action of hallucinogenic drugs of abuse at the cellular/molecular level of detail. The collaborative efforts represent a multidisciplinary approach to the exploration of structure-function relations of 5-HT receptors with the methods of molecular biology. and coordinated assessments of discriminant pharmacological characteristics and interactions of hallucinogens with the methods of molecular pharmacology. To achieve the goals of the theoretical components of this IRPG, the following interrelated steps will be taken: l. Complete three dimensional molecular models of the 5-HT2A and 5-HT2C receptors and their complexes with hallucinogens and non-hallucinogens will be constructed. 2. The dynamics of ligand/receptor complexes with the models of the 5-HT2A and 5-HT2C receptors will be simulated computationally to examine the time-dependent elements of the receptor recognition process for agonist vs. antagonist pairs, and hallucinogen vs. non-hallucinogen pairs, and in order to identify changes in receptor structure related to the signal transduction mechanisms produced by the various pairs of compounds. 3. Computational modeling and dynamic simulation will be used to learn the structural basis for the special ligand/receptor interaction properties of other 5-HT receptor subtypes putatively implicated in the actions of hallucinogenic drugs of abuse, e.g.. the 5-HT6 receptor which is a putative target for hallucinogenic compounds in the class of """"""""tricyclic psychotropic drugs"""""""". Structure-function relations of both the ligands and the receptors will be explored in the theoretical constructs and, in parallel, experimentally. Mutant receptor constructs and pharmacological assays suggested by the results of the computational studies will be performed in the collaborative aspects of the IRPG.
Showing the most recent 10 out of 23 publications
