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Interaction of drugs amlodipine and paroxetine with the metabolizing enzyme CYP2B4: a molecular dynamics simulation study

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Abstract

The interactions of the drugs amlodipine and paroxetine, which are prescribed respectively for treatment of hypertension and depression, with the metabolizing enzyme cytochrome CYP2B4 as the drug target, have been studied by molecular dynamics (MD) simulation. Poly ethylene glycol was used to control the drugs’ interactions with each other and with the target CYP2B4. Thirteen simulation systems were carefully designed, and the results obtained from MD simulations indicated that amlodipine in the PEGylated form prescribed with paroxetine in the nonPEGylated form promotes higher cytochrome stability and causes fewer fluctuations as the drugs approach the target CYP2B4 and interact with it. The simulation results led us to hypothesize that the combination of the drugs with a specific drug ratio, as proposed in this work, manifests more effective diffusivity and less instability while metabolizing with enzyme CYP2B4. Also, the active residues in the CYP2B4 enzyme that interact with the drugs were determined by MD simulation, which were consistent with the reported experimental results.

Efficient drug-enzyme interactions, as a result of PEGylation.

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Authors and Affiliations

  1. Department of Chemical Engineering, Amirkabir University of Technology (Tehran Polytechnic), 424 Hafez Ave, Tehran, Iran

    Abbas Yousefpour, Hamid Modarress & Sepideh Amjad-Iranagh

  2. Department of Polymer Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran

    Fatemeh Goharpey

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  1. Abbas Yousefpour
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  2. Hamid Modarress
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Correspondence to Hamid Modarress.

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Electronic supplementary material

Fig. 1

The structures and chemical names of: (a) amlodipine, (b) paroxetine, and (c) PEG (GIF 86 kb)

High resolution image (TIFF 81 kb)

Fig. 2

The agglomeration of the drugs, AML and PAR (GIF 488 kb)

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Fig. 3

Root mean square fluctuation (RMSF) of CYP for simulation systems S1 (GIF 82 kb)

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Fig. 4

Root mean square fluctuation (RMSF) of CYP for simulation systems S2 (GIF 89 kb)

High resolution image (TIFF 146 kb)

Fig. 5

Root mean square fluctuation (RMSF) of CYP for simulation systems S4 (GIF 82 kb)

High resolution image (TIFF 128 kb)

Fig. 6

Root mean square fluctuation (RMSF) of CYP for simulation systems S5 (GIF 85 kb)

High resolution image (TIFF 136 kb)

Fig. 7

Root mean square fluctuation (RMSF) of CYP for simulation systems S7 (GIF 68 kb)

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Fig. 8

Root mean square fluctuation (RMSF) of CYP for simulation systems S8 (GIF 115 kb)

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Fig. 9

Root mean square fluctuation (RMSF) of CYP for simulation systems S9 (GIF 79 kb)

High resolution image (TIFF 121 kb)

Fig. 10

Root mean square fluctuation (RMSF) of CYP for simulation systems S10 (GIF 69 kb)

High resolution image (TIFF 101 kb)

Fig. 11

Root mean square fluctuation (RMSF) of CYP for simulation systems S11 (GIF 79 kb)

High resolution image (TIFF 123 kb)

Fig. 12

Root mean square fluctuation (RMSF) of CYP for simulation systems S12 (GIF 77 kb)

High resolution image (TIFF 118 kb)

Fig. 13

Root mean square fluctuation (RMSF) of CYP for simulation systems S13 (GIF 86 kb)

High resolution image (TIFF 136 kb)

Fig. 14

Root mean square deviation (RMSD) of CYP for simulation systems S1 (PNG 15 kb)

Fig. 15

Root mean square deviation (RMSD) of CYP for simulation systems S2 (PNG 17 kb)

Fig. 16

Root mean square deviation (RMSD) of CYP for simulation systems S4 (PNG 16 kb)

Fig. 17

Root mean square deviation (RMSD) of CYP for simulation systems S5. (PNG 15 kb)

Fig. 18

Root mean square deviation (RMSD) of CYP for simulation systems S7 (PNG 15 kb)

Fig. 19

Root mean square deviation (RMSD) of CYP for simulation systems S8 (PNG 15 kb)

Fig. 20

Root mean square deviation (RMSD) of CYP for simulation systems S9 (PNG 15 kb)

Fig. 21

Root mean square deviation (RMSD) of CYP for simulation systems S10 (PNG 15 kb)

Fig. 22

Root mean square deviation (RMSD) of CYP for simulation systems S11 (PNG 15 kb)

Fig. 23

Root mean square deviation (RMSD) of CYP for simulation systems S12 (PNG 15 kb)

Fig. 24

Root mean square deviation (RMSD) of CYP for simulation systems S13 (PNG 16 kb)

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Yousefpour, A., Modarress, H., Goharpey, F. et al. Interaction of drugs amlodipine and paroxetine with the metabolizing enzyme CYP2B4: a molecular dynamics simulation study. J Mol Model 24, 67 (2018). https://doi.org/10.1007/s00894-018-3617-8

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