Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 8, Pages 3805-3814Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00300
Keywords
Translocator protein 18 kDa; neuroactive steroids; residence time; molecular dynamics; unbinding event; potential of mean force
Funding
- University of Campania Luigi Vanvitelli (VALERE PLUS Project)
- MIUR-PRIN 2015 [2015FCHJ8E_003]
- University of Pisa (PRA Project) [PRA_2018_20]
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Translocator protein 18 kDa (TSPO) is a validated pharmacological target for the development of new treatments for neurological disorders. N,N-Dialkyl-2-phenyl-indol-3-ylglyoxylamides (PIGAs) are effective TSPO modulators and potentially useful therapeutics for the treatment of anxiety, central nervous system pathologies featuring astrocyte loss, and inflammatory-based neuropathologies. For this class of compounds, no correlation exists between the TSPO binding affinity and the corresponding functional efficacy. Rather, their biological effectiveness correlates with the kinetics of the unbinding events and more specifically with the residence time (RT). So far, the structural reasons for the different recorded RT of congeneric PIGAs remain elusive. Here, to understand the different kinetics of PIGAs, their unbinding paths were studied by employing enhanced-sampling molecular dynamics simulations. Results of these studies revealed how subtle structural differences between PIGAs have a substantial effect on the unbinding energetics. In particular, during the egress from the TSPO binding site, slow-dissociating PIGAs find tight interactions with the protein LP1 region thereby determining a long RT. Further support to these findings was achieved by in vivo studies, which demonstrated how the anxiolytic effect observed for the inspected PIGAs correlated with their RT to TSPO.
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