A Computational Analysis of Select Antipsychotics’ Docking Interactions with D2 and D3 Receptors and Their Correlation with Extrapyramidal Symptoms’ Prevalence

Abstract

Antipsychotic Drugs (APDs) are the standard treatment for schizophrenia, and while they cannot cure it, they do minimize symptoms to improve patients’ quality of life. However, APDs are known to cause extrapyramidal symptoms (EPS) as side effects. APDs mostly work as antagonists, lowering dopamine production in the brain. This means when an APD is too strong, it causes a dopamine deficiency similar to the one seen in Parkinson’s patients, thus producing EPS which mimic Parkinson’s symptoms. This study used Chimera to execute receptor comparisons, AutoDock for running docking simulations to gather quantitative data, and VMD to represent this data for analysis. These experimental steps did not yield the expected results, as the predicted D2 to D3 binding energy ratio demonstrated no correlation with EPS likelihood. However, a notable drop in EPS was correlated with a large spike in the total number of docked poses available to a drug. Clozapine was the drug demonstrating this spike, and was notably the smallest compound being tested. This indicates a likely relationship between the quantity of available docked poses and the percentage of patients demonstrating EPS. This relationship is attributed to the short-term binding exhibited by drugs that have many available docked conformations.