Computational analyses of curcuminoid analogs against kinase domain of HER2
© Yim-im et al.; licensee BioMed Central Ltd. 2014
Received: 3 February 2014
Accepted: 28 July 2014
Published: 3 August 2014
Human epidermal growth factor receptor 2 (HER2) has an important role in cancer aggressiveness and poor prognosis. HER2 has been used as a drug target for cancers. In particular, to effectively treat HER2-positive cancer, small molecule inhibitors were developed to target HER2 kinase. Knowing that curcumin has been used as food to inhibit cancer activity, this study evaluated the efficacy of natural curcumins and curcumin analogs as HER2 inhibitors using in vitro and in silico studies. The curcumin analogs considered in this study composed of 4 groups classified by their core structure, β-diketone, monoketone, pyrazole, and isoxazole.
In the present study, both computational and experimental studies were performed. The specificity of curcumin analogs selected from the docked results was examined against human breast cancer cell lines. The screened curcumin compounds were then subjected to molecular dynamics simulation study. By modifying curcumin analogs, we found that protein-ligand affinity increases. The benzene ring with a hydroxyl group could enhance affinity by forming hydrophobic interactions and the hydrogen bond with the hydrophobic pocket. Hydroxyl, carbonyl or methoxy group also formed hydrogen bonds with residues in the adenine pocket and sugar pocket of HER2-TK. These modifications could suggest the new drug design for potentially effective HER2-TK inhibitors. Two outstanding compounds, bisdemethylcurcumin (AS-KTC006) and 3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (AS-KTC021 ),were well oriented in the binding pocket almost in the simulation time, 30 ns. This evidence confirmed the results of cell-based assays and the docking studies. They possessed more distinguished interactions than known HER2-TK inhibitors, considering them as a promising drug in the near future.
The series of curcumin compounds were screened using a computational molecular docking and followed by human breast cancer cell lines assay. Both AS-KTC006 and AS-KTC021 could inhibit breast cancer cell lines though inhibiting of HER2-TK. The intermolecular interactions were confirmed by molecular dynamics simulation studies. This information would explore more understanding of curcuminoid structures and HER2-TK.
KeywordsHER2 Tyrosine kinase Curcuminoid analogs Docking Molecular dynamics simulation
Human Epidermal Growth Factor Receptor 2 (HER2) is one of the tyrosine kinase receptors in EGFR family, which includes EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 . Since there is no natural ligand specific to HER2, HER2 tends to form heterodimer with other ligand-induced members . After dimerization, the complex can trigger downstream pathways such as Ras/Raf/MAPK and PI3K/AKT pathways to increase cell growth, cell survival and cell differentiation [3, 4]. Considerable evidencesshowed that HER2 over expression was involved in many types of cancer such as breast, ovarian, gastric and prostate cancers . Therefore, HER2 is considered as a drug target for cancer therapy focusing on inhibiting HER2 to reduce tumor growth.
At present, there are two main approaches used to inhibit HER2, namely; monoclonal antibodies such as Trastuzumab, and small molecule inhibitors such as Lapatinib  and SYR127063 (called SYR for short)  targetingon tyrosine kinase domain (HER2-TK). Although Trastuzumab can downregulate HER expression, cardiotoxicity and drug resistance can be found in Trastuzumab-treated patients [8, 9]. Moreover, side effects such as diarrhea, rash or nausea can be observed in Lapatinib treatment . Hence, new inhibitors are urgently required for HER2-overexpressed cancer treatment.
Recently, in 2011, the first HER2-TK structure complex with pyrimidine compound SYR was released (PDB access 3PP0), providing the new understanding of the kinase structure . Unlike the active- or inactive-conformations of EGFR-TK, HER2-TK configuration was somewhat in the middle of these typical conformations. It was named “the active-like conformation”, due to, the orientation of the helix-αC-out, the DFG-in and unformed secondary structure of the activation loop. The second crystal of HER2-TK complex with TAK-285 (PDB access 3RCD) adopted the similar conformation as mentioned above .
Curcumin (also known as diferuloylmethane) is generally found as the major compound in rhizomes of turmeric plants; Curcuma longa Linaeusas yellow residue. It has been used as spice and ingredients in folk medicinal remedies in many Asian countries. The curcumin and its three natural analogs, curcumin II (demethoxycurcumin), curcumin III (bisdemethoxycurcumin) and cyclocurcuminpossess the remarkable pharmacological effects for centuries, such as anti-inflammatory [12, 13], antioxidant , anti-carcinogenesis [15–18]. Moreover, curcumins is safe to use in high dose with non-toxic report [19, 20]. Despite many advantages of curcumins, the poor stability and bioavailability profiles of curcumins are questionable when it comes to directly using crude curcumin as the potent and selective cancer drug. Many researchers have been focusing on the developing the curcumin analogs to enhance their stability and bioavailability. In particular, the novel series of curcumin-analog compounds have been synthesized and studied their effect in various cell targets [21–26]. They possess several properties, potent activity against parasite in Trypanosoma and Leishmania species , antimycobacterial activity , inhibiting nitric oxide production from Lps-activated microglial cells  and estrogenic properties [23, 24, 26]. Thus, in this paper, we aimed to investigate the effect of this set of curcumin analogs on the HER2-TK activity using both experimental and computational methods.
Curcumin has been shown to inhibit cancer growth by means of inhibiting several tyrosine kinases including EGFR, HER2, MAPK, phosphorylase kinase, pp60c-src tyrosine kinase, protein kinase C, and protein kinase A [18, 27–34]. Furthermore, the curcumins can inhibit various types of cancer including breast cancer cells [15, 28] and also induce the internalization of HER2 from cell surface . Recently, curcumin analog cyclohexanone has shown to selectively inhibit tyrosine kinase domain of EGFR, in vitro, in vivo and in silico studies  which reveals an opportunity for direct binding between curcumins and tyrosine kinase domains of other EGFR family members. Furthermore, the in silico screening of the natural database against HER2 kinase showed that such curcumins could interact with kinase through benzene rings for hydrophobic interactions and carboxyl groups for hydrogen bond formation .
In this study, we investigated interactions between curcumin analogs and HER2-TK by using virtual screening based on molecular docking in order to find potential compounds against HER2-TK. The hit compounds have been validated by different inhibitions between two types of breast cancer cell-lines with both HER2-overexpression and HER2-non-overexpression. Such findings might be useful for further development of curcumins as a new HER2 inhibitor in the future.
The preparation of ligand
The two dimensional (2D) structure of 143 curcuminoid analogs were collected from the previous studies [21–26] (Additional file 1: Table S1). The ionization states, tautomers, stereochemistries, and ring conformations of all curcuminoid structures were calculated and OPLS-2005 force field was applied using LigPrep module in Schrödinger package. These structures were used as an initial material during computational docking procedure to study interactions with the binding site of the HER2 tyrosine kinase domain.
The preparation of protein
The atomic coordinate of HER2 tyrosine kinase domain (HER2-TK) was obtained from the crystallographic structure, accession no. 3PP0 in Protein Data Bank (PDB) . This structure contains asymmetric dimer of HER2-TK complex with selective inhibitor HER2-TK, pyrrolo[3,2-d]pyrimidine-based potent, SYR. In order to perform the docking calculations, only chain A was selected as the target template. Another chain of HER2-TK as well as the co-crystalized ligand(s) and crystal water molecules were removed. Hydrogen atoms were assigned and parameterized with Optimized Potential for Liquid Simulation version 2005 (OPLS-2005 force field) using the protein preparation wizard, which continuously minimized the whole structure by the Impref module in the Schrödinger package.
Docking procedure using Glide standard precision mode (SP mode)
The structures of protein and ligands were prepared as previously described. The OPLS-2005 force field was applied to both protein and ligands. The complexes of HER2-TK and each curcuminoid, including the co-crystal ligand were generated with molecular docking approach using Grid-based Ligand Docking with Energetics (Glide)with standard precision mode (SP mode) [38, 39]. The grid map was generated in Receptor Grid Generation by setting the center of the grid map around the catalytic site. Self-docking between HER2-TK and SYR was performed to validate all parameters before being applied to the study of interactions between HER2 and curcumins.
In order to handle considerable number of docking results, the sub-groups of modified core structure of curcuminoids were classified. Top ranks docking score of each sub-group were selected to further test in cell-based assay. In addition, the poor scores of each curcumin sub-groups were also chosen to be the control set in breast cancer cell-line assay.
Molecular interaction and stability in binding pocket
All simulation steps were performed using the SANDER module of the AMBER 12 package and AMBER FF03 force-field parameters . The partial atomic charges of ligand were computed by using AM1-BCC method as implemented in the Antechamber module of the AMBER package. Their atom types and missing force field parameters were assigned based on the general AMBER force field (GAFF). Each complex was immersed in an isomeric truncated-octahedron box of TIP3P water molecules (10 Å from the solute surface) and neutralized by additional Cl- anions. The system was then minimized with the five-step procedure (Additional file 1: Table S2). All steps included 5,000 steepest-descent minimization cycles and 5,000 conjugate-gradient minimization cycles with different restraints on the protein structure. For the first step, harmonic restraints with a force constant of 5 kcal/(mol · Å2) were used to immobilize the heavy atoms of protein coordinates, excluding hydrogen atoms, at the starting positions, while solvent molecules were allowed to relax the unfavorable contacts with other solvent and solute molecules. For the second, third and fourth steps, harmonic restraints with force constants of 5, 1 and 0.5 kcal/(mol · Å2), respectively, were used to restrain the backbone of the protein. In the last step, the entire system was minimized with no positional restraints.
With weak positional restraints on the protein (force constant of 5 kcal/(mol · Å2)), all systems were heated from 0 to 300 K during a 200 ps MD simulations. After removing the restraints from the protein, we equilibrated the system with constant volume and set the constant temperature at 300 K for 500 ps. Note that we observed the equilibrium of energy (potential, kinetic and total energy), temperature, pressure, volume, density and RMSD before moving on to the production runs. The production MD simulations were performed from 30 ns while maintaining constant pressure and temperature. With a collision frequency of 1 ps-1, the temperature in all simulations was controlled by Langevin dynamics. Using an isotropic position scaling algorithm with a relaxation time of 2 ps, the pressure in NPT simulations was maintained at an average pressure of 1 atm. The random number generator was reseeded  for every simulation. A cut-off of 10 Å and the particle mesh Ewald method were employed with the default parameters to calculate long-range non bonded interactions. With the tolerance parameter of 10-5 Å, SHAKE constraints  were used to eliminate bond-stretching freedom for all bonds involving hydrogen, thereby allowing the use of a 2 fs time step. To monitor the stabilities of all systems, the Cα root-mean-square deviations (RMSD) were calculated. The RMSD of binding residues within 5 Å of the inhibitor were examined. The ptraj modules in the AMBER software were used to calculate the hydrogen bond occupancy and hydrogen bond distance between inhibitors and proteins [43, 44]. All MD simulations were calculated on 22-node Linux High Performance Computer Cluster with 32 cores of AMD 2.2 GHz.
‹∆GMMPBSA› is referred to final calculated MM-PBSA binding energy. It is described by the difference of ΔGcomplex by the summation of ΔGprotein and ΔGligand (1). The free energy of each molecular system is given by the expression in the terms of equation (2). ‹∆EMM› is the total molecular mechanics energy in the gas phase, ‹∆Gsolv› is a correction term (solvation free energy) of each system surrounded by solvent, and ‹T∆S› is the entropy. ‹∆EMM› includes electrostatic ‹∆Eele›, and van der Waals ‹∆Evdw› energies, while ‹∆Gsolv› is the sum of electrostatic solvation energy ‹∆Gpb›, and the non-electrostatic solvation component ‹∆Gnp› (3–4). The polar contribution is calculated using PB model, while the non-polar energy is estimated by solvent accessible surface area (SASA). In this study, ‹T∆S› term was excluded.
Proliferation and viability assay
Absorbance of vehicle control well.
All curcumin analog compounds were synthesized and published [21–26] by the laboratory of Prof. Dr. Apichart Suksamran, Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University.
Results and discussion
Selection of the curcumin analogs and structure analyses
Two dimensional structures of curcumin analogs and its Gscore
The bioavailability profiles of curcumin analogs on two types of human breast cancer cell lines
The inhibitory activity profiles of curcumin analogs on MCF7 and SKBR3 cells
8.3 ± 0.6
41.9 ± 12.3
13.0 ± 1.8
44.4 ± 10.8
10.8 ± 5.5
9.9 ± 3.5
24.9 ± 2.3
81.6 ± 26.0
30.9 ± 4.5
15.4 ± 3.8
79.4 ± 9.8
42.6 ± 5.5
33.8 ± 5.8
21.3 ± 3.8
14.3 ± 1.9
15.4 ± 3.9
33.8 ± 7.2
22.4 ± 7.7
7.9 ± 2.5
17.5 ± 4.5
38.9 ± 9.1
7.9 ± 2.5
36.7 ± 5.8
25 ± 5.5
44.1 ± 9.0
8.2 ± 0.4
22.1 ± 0.1
16.9 ± 3.4
24.3 ± 8.7
9.9 ± 1.0
14.3 ± 1.6
Molecular interaction, stability binding free energy via MM-PBSA
Conclusion of H-bonds between compounds and tyrosine kinase of HER2
3.128 ± 0.15
2.761 ± 0.17
2.851 ± 0.18
3.191 ± 0.18
2.758 ± 0.16
3.142 ± 0.18
3.100 ± 0.20
Individual terms of MM-PBSA binding energy (kcal mol -1 ), entropy term excluded
In the present study, we screened a series of curcumin compounds using a computational molecular docking. Then, the bioavailability assay of curcumin analogs, were conducted on two types of human breast cancer cell lines to select the specific active HER2 kinase inhibitors. The results suggested that bisdemethylcurcumin compound (AS-KTC006, CAS no. 60831-46-1) and 3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (AS-KTC021, CAS no. 1118765-46-0) could inhibit breast cancer cell lines though HER2-TK. In addition, the intermolecular studies from MD simulation suggested that both selected curcumin analogs form the distinguish interaction moiety from the known inhibitors of HER2-TK. MM-PBSA binding calculation suggested that non-polar contributions are not only significant with all ligand(s)-HER2TK systems but also a major factor of the ligand-protein interactions.
Human Epidermal Growth Factor Receptor 2
Epidermal Growth Factor Receptor
Tyrosine kinase domain of HER2
Grid-based Ligand Docking with Energetics
- SP mode:
Standard precision mode
Bisdemethylcurcumin, also called Di-O-demethylcurcumin, Bis(3,4-Dihydroxy-trans-cinnamoyl)methane (CAS no. 60831-46-1)
3,5-bis((E)-3,4-dimethoxystyryl)isoxazole (CAS no.1118765-46-0)
A breast cancer cell line which over-expresses the HER2 gene product
A breast cancer cell line that absence of HER2 protein overexpression.
This work was supported by Faculty of Science and Grad School Research Fund, Kasetsart University, Kasetsart University Research and Development Institute, and National Research University Project of Thailand, the Office of the Higher Education Commission. We would like to thank Prof. Peter Wolschann, Institute of Theoretical Chemistry, University of Vienna, Austria for providing the Schrödinger programs and the National Center for Genetic Engineering and Biotechnology (BIOTEC) and the National Science and Technology Development Agency (NSTDA) for the use of high performance computer clusters.
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