Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin

Abstract

Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many downstream physiological responses, including muscle contraction, learning and depression. The antipsychotic drug trifluoperazine (TFP) is a known CaM inhibitor. By binding to various sites, TFP prevents CaM from associating to target-proteins. However, the molecular and state-dependent mechanisms behind CaM inhibition by drugs such as TFP are largely unknown. Here, we build a Markov state model (MSM) from adaptively sampled molecular dynamics simulations and reveal the structural and dynamical features behind the inhibitory mechanism of TFP-binding to the C-terminal domain of CaM. We specifically identify three major TFP binding-modes from the MSM macrostates, and distinguish their effect on CaM conformation by using a systematic analysis protocol based on biophysical descriptors and tools from machine learning. The results show that depending on the binding orientation, TFP effectively stabilizes features of the calcium-unbound CaM, either affecting the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the bound domain. The conclusions drawn from this work may in the future serve to formulate a complete model of pharmacological modulation of CaM, which furthers our understanding of how these drugs affect signaling pathways as well as associated diseases.

Insights into mode of action mediated responses following pharmaceutical uptake and accumulation in plants

“…Phenothiazines, as one of the most common antipsychotic classes of pharmaceuticals, are known calmodulin inhibitors, and are also known to be persistent to conventional wastewater treatment and as such are often detected in wastewaters which can enter the environment (El-Azazy, 2023). Antipsychotic phenothiazines such as trifluoperazine and fluphenazine may become even more widely used as they are currently being studied for their potential in cancer treatment and as an antiretroviral (Manoharan et al, 2022;Mao et al, 2022;Westerlund et al, 2022). Therefore, they should be further studied in terms of their potential to elicit sub-lethal effects in plants.…”