AbstractThe aim of this study is to investigate the computer-aided prediction of pharmacological activity and mechanisms of action of 6-[4-methoxy-3-(1H-pyrazol-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[22.214.171.124]tetradecane-4,8,12-trione (TCT-9). The compound was designed for modulation of ionotropic glutamate AMPA receptors, and its affinity for the receptor has been earlier proven experimentally. A cognitive stimulating effect of TCT-9 has been shown using a model of freezing behavior in mice. The drug candidate TCT-9 is now under the development process: it is intended for the treatment of cognitive impairments in case of brain injury. Following the existing requirements, the present study was carried out in the framework of secondary pharmacodynamic studies to determine possible off-target effects and interaction of the compound with regulatory signaling and metabolic networks/pathways. In silico study of the TCT-9 binding to pharmacologically significant targets and the new AMPA receptor modulator's effects on signaling pathways was carried out by the analysis of structure-activity relationships. Prediction of biological activity spectra was performed using PASS (Prediction of Activity Spectra for Substances), which estimates the probabilities for more than five thousand biological activities. The PharmaExpert program assessed information on the belonging of the targets predicted by the PASS program to the signaling and metabolic pathways. The prediction results are the basis for the experimental verification of the binding of the TCT-9 to the steroid hormone receptor ERR1 and further studies of the drug activity in animal models of diseases.
In silico profiling of the new allosteric modulator of AMPA receptors / G. Brkich, N. Pyatigorskaya, O. Zyryanov, T. Melnikova, N. Tuaeva // Georgian Medical News. – 2022. – № 2 (323). – P. 151-156.