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Exploration of the binding of curcumin analogues to human P450 2C9 based on docking and molecular dynamics simulation

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Abstract

Molecular docking and molecular dynamics (MD) simulations are used to investigate the interactions of curcumin analogues (CAs) with human cytochrome P450 2 C9 (CYP2C9 or 2 C9) and the conformations of their binding sites. In order to examine conformations of CAs/2 C9 and interaction characteristics of their binding sites, RMSDs, RMSFs, and B-factors are computed, and electrostatic and hydrophobic interactions between CAs and 2 C9 are analyzed and discussed. Results demonstrate that the most CAs studied lie 4 ∼ 15 Å above the heme of CYP2C9. The presence of CAs makes some residues in bound CYP2C9s become more flexible. In the binding sites of A0/2 C9 and C0/2 C9, the formation of H-bond networks (or CA-water-residue bridges) enhances the interactions between CAs and 2 C9. The stronger inhibitory effects of A0, B0, and C0 on 2 C9 can be ascribed to stronger electrostatic and hydrophobic interactions in the binding sites of CAs/2 C9.

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Acknowledgments

This work is supported by grants from the National Science Foundation of China (No. 20236010, 20246002, 20376032, 20706029, and 20876073), Jiangsu Science and Technology Department of China (No. BK2008372), and Nanjing University of Technology of China(No. ZK200803). We want to express our thanks for the Reviewers’ valuable suggestions for this article.

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  1. State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing University of Technology, Nanjing, 210009, China

    Rongwei Shi, Yin Wang, Xiaolei Zhu & Xiaohua Lu

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  1. Rongwei Shi
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Correspondence to Xiaolei Zhu or Xiaohua Lu.

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Fig. SI-1

Chemical structures of curcumins. (DOC 41 kb)

Fig. SI-2

Most favorable docking conformations of CAs in the binding site of CYP2C9. The curcumin analogues and heme group are shown in sticks. The Fe atom in heme group is represented in ball. Carbon atoms of CAs are colored in magenta (A0), yellow (B0), silvery white (B12), orange (C0), forest (C2). The A, F, F’, G’, G and I helix around CAs are labeled as orange. (DOC 583 kb)

Fig. SI-3

Residue fluctuations (as represented by RMSFs) obtained by averaging atomic fluctuations over the last 4-ns simulation for 2C9/A0 (A), 2C9/B0 (A), 2C9/C0 (A), 2C9/B12 (B), and 2C9/C2 (B) complexes. For comparison, the RMSF of free 2C9 is also shown in (A) and (B). In the two graphs, the highly flexible loops are highlighted. (DOC 194 kb)

Fig. SI-4

The experimental residue B-factors (red curve) of 2C9 obtained from X-ray crystal structure and calculated values of bound 2C9 (black curve) from the last 3ns-MD simulations. (DOC 109 kb)

Fig. SI-5

Snapshots of the hydrogen bond networks in the binding site of 2C9/A0 at 2ns (a), 2.5ns (b), 6ns (c), 8ns (d) and 10ns (e), respectively. Carbon atoms of residues and A0 are colored in green and marine, respectively. Each dotted line (black) indicates a hydrogen bond. (DOC 1017 kb)

Fig. SI-6

Snapshots of the hydrogen bonds in the binding site of CYP2C9-B0 at 0ns, 2ns, 6ns, 8ns, 10ns. Carbon atoms of residues and A0 are colored in green and marine, respectively. Each dotted line (black) indicates a hydrogen bond. (DOC 704 kb)

Fig. SI-7

(a) Two-dimensional schematic representation of hydrogen- bond and hydrophobic interactions for the binding site of CYP2C9/B12. Red balls represent the oxygen atoms of residues or waters. Black balls and blue balls indicate the carbon atoms and nitrogen atoms of residues, respectively. Spiked residues form hydrophobic interactions. (b) The mass-center distances of hydrophobic residues (G296, F476, L362, F100, A103) with one side benzene ring (ben), center cyclopentanone group (pent), one substituted methyl group (CH3) in benzene ring of B12 with time evolution. (DOC 98 kb)

Fig. SI-8

(a) Two-dimensional schematic representation of hydrogen bond and hydrophobic interactions for the binding site of CYP2C9/C2. Red balls represent the oxygen atoms of residues or waters. Black balls and blue balls display the carbon atoms and nitrogen atoms of residues, respectively. Dashed lines represent hydrogen bonds and spiked residues form hydrophobic interactions. (b) The H-bond distances between O13 of C2 and a water (W3328) with time evolution. (c) The mass-center distances of hydrophobic residues (L233, A103, L102, F69, L208, F114) with two terminal benzene rings (ben1 and ben2), one side carbon chain (chain) of C2 versus time. (DOC 130 kb)

Fig. SI-9

Final conformations for the binding sites of B12/CYP2C9 (a), C0/CYP2C9(b), and C2/CYP2C9(c). Carbon atoms of CYP2C9 and ligands are colored in limon and green, respectively. Each dotted line (black) indicates a hydrogen bond. The residues and waters surrounding binding sites are shown in sticks. (DOC 469 kb)

Fig. SI-10

Electrostatic potentials (-1 to +1 kT/e) for binding sites of (a) B12/2C9, (b)C0/2C9 and (c)C2/2C9. Red, blue, and white represent negative, positive, and neutral regions, respectively. (DOC 366 kb)

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Shi, R., Wang, Y., Zhu, X. et al. Exploration of the binding of curcumin analogues to human P450 2C9 based on docking and molecular dynamics simulation. J Mol Model 18, 2599–2611 (2012). https://doi.org/10.1007/s00894-011-1275-1

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