Molecular Dynamics Simulations of Neutral Chlorpromazine in Zwitterionic Phospholipid Monolayers

Abstract

Molecular dynamics simulations have been performed to investigate the interactions between chlorpromazine (CPZ), a neuroleptic drug used in the treatment of psychiatric disorders, and dipalmitoylphosphatidylcholine (DPPC), a zwitterionic phospholipid, in Langmuir monolayers. The results from simulations carried out at different monolayer surface densities were able to capture important features of the CPZ-lipid interaction. We find that neutral (unprotonated) CPZ is preferentially located in the lipid tail region of the phospholipids, in little contact with the aqueous phase, and that the orientation of its rigid ring structure and tail conformation vary with lipid surface density. CPZ is found to promote ordering of the lipid tails for all surface densities because of a reduction in the effective surface area per lipid upon addition of the drug. Similar effects have been observed in previous studies of cholesterol in DPPC monolayers, in which lipid tails were seen to order around the solute. This feature, however, is quite distinct from what we observe for the most dense monolayer considered here (area per lipid of 50 A(2)), for which we find that CPZ promotes a local distortion of the lipid tails in its immediate vicinity and a concomitant ordering of lipid tails located further away from the solute. This view is further supported by the results obtained for an approximated nonlinear vibrational sum frequency generation susceptibility, which showed greater tail disorder close to CPZ.

Modification of membrane heterogeneity by antipsychotic drugs: An X-ray diffraction comparative study

“…They were all able to induce significant changes in d-spacing, d w and d pp values as evaluated by XRD methods. Results obtained from our studied CPZ sample are in accordance with data published in the ordering effect described with polyunsaturated lipids [10][11][12][13]. Similarly, the observed Lo d pp decrease is in agreement with the CPZ disordering effect seen in DMPC/cholesterol samples [10].…”

“…Similarly, the observed Lo d pp decrease is in agreement with the CPZ disordering effect seen in DMPC/cholesterol samples [10]. A molecular understanding of these results suggests that the hydrophobic CPZ tricyclic ring structure partitions with relative ease into the bulk hydrocarbon phase of membrane bilayers, while its polar propylamine tail region which is hydrophilic, interacts with phospholipids polar head groups [12,13]. CPZ is also known to interact with negatively charged glycerophospholipids [3,12,14].…”

CHARMM‐based parameterization of neutral articaine—A widely used local anesthetic

“…From a theoretical perspective, atomistic molecular dynamics (MD) computer simulations are being successfully applied to investigate the effects of various LAs on model phospholipidic membranes at a molecular level18–23. However, because of the wide variety of these compounds, it is often needed to develop new interaction potential parameters that allow the study of these systems by MD simulations.…”

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…The studied flavonoids belonged to different subgroups (see Fig. 2): flavanone glycosides (neohesperidin (48), hesperidin (47), naringin (49)), flavanone aglycones (galangin (27), hesperetin (34), naringenin (33)), flavone glycosides (rutin (50)), and flavone aglycones (flavone (21), chrysin (22), fisetin (32), kaempferol (28), morin (30), quercetin (29), myricetin (31), apigenin (23)). Also, furanocoumarin (bergapten (69), methoxalen (70), psoralen (68)) and coumarin derivatives (scopoletin (72), umbelliferone (73), coumarin (71), 7-ethoxycoumarin (74)) were studied (see Fig.…”

“…Molecular dynamics simulations have been performed to investigate the interactions between CPZ (9) and DPPC in Langmuir monolayers [48]. The results of computer simulations revealed that the unprotonated form of the drug is preferentially located in the lipid tail region of the phospholipids, having little contact with the aqueous phase.…”