Assessment of new anti-HER2 ligands using combined docking, QM/MM scoring and MD simulation

Ahmed, Marawan; Sadek, Maiada M.; Serrya, Rabah A.; Kafafy, Abdel-Hamid N.; Abouzid, Khaled A. M.; Wang, Feng

doi:10.1016/j.jmgm.2012.12.001

Cited by 19 publications

(25 citation statements)

References 31 publications

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“…The consistent observations were presented in all three different computational approaches, namely, focusing on O-atom of ketone to interact with Thr862 of the system AS-KTC006-HER2TK complex. Recently, the computational model of anti-HER2 ligands, the analogous of 4-anilinoquinazoline were reported [57, 58]. These works showed that the vdW term could be a major factor of the ligand-protein interactions; hence, the deep hydrophobic pocket would be the selectivity pocket of HER2-TK [57, 58].…”

Section: Resultsmentioning

confidence: 99%

“…Recently, the computational model of anti-HER2 ligands, the analogous of 4-anilinoquinazoline were reported [57, 58]. These works showed that the vdW term could be a major factor of the ligand-protein interactions; hence, the deep hydrophobic pocket would be the selectivity pocket of HER2-TK [57, 58]. Rather than focusing on the 4-anilinoquinazoline core structure (the known HER2-TK inhibitors), we focused on the curcuminoid core structure in this study.…”

Section: Resultsmentioning

confidence: 99%

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Computational analyses of curcuminoid analogs against kinase domain of HER2

et al. 2014

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BackgroundHuman 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.ResultsIn 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2105-15-261) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Computational analyses of curcuminoid analogs against kinase domain of HER2

et al. 2014

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“…More importantly, the resulting MD trajectories allowed us to accurately measure the binding affinities for the predicted complexes using the molecular mechanic-Poisson Boltzmann surface area (MM-PBSA) method [21][22][23][24][25][26][27][28]. The MM-PBSA method has been successfully applied in several drug design related studies [35][36][37][38][39][40][41][42]. We also included for this analysis two models of PD-1/PD-L1 and PD1/PD-L2 that were constructed by superimposing the human PD-1, PD-L1 and PD-L2 on the reported mouse crystal structures for each protein-protein complex similar to the same procedure as described in Cheng's study [20].…”

Section: Refining the Docked Structures And Their Final Rankingmentioning

confidence: 99%

Human PD-1 binds differently to its human ligands: A comprehensive modeling study

Viricel

Ahmed

Barakat

2015

Journal of Molecular Graphics and Modelling

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“…The crystal structure of the Chikungunya virus nsP2 protease was downloaded from the protein data bank (PDB ID: 3TRK). The protein preparation wizard in Maestro was used to repair the protein, adding missing residues and saturate with hydrogens, similar to what have been described in our previous studies . The geometries of the ligands were optimized at the RM1 level of theory as implemented in the schrodinger package .…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel Peptidomimetics as Irreversible CHIKV NsP2 Protease Inhibitors Using Quantum Mechanical‐Based Ligand Descriptors

et al. 2015

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Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections have been reported in Asia, Africa, and Europe. The symptoms of CHIKV infection include fever, headache, nausea, vomiting, myalgia, rash, and chronic persistent arthralgia. To date, no vaccines or selective antiviral drugs against this important emerging virus have been reported. In this study, the design, synthesis, and antiviral activity screening of new topographical peptidomimetics revealed three potential prototype agents 3a, 4b, and 5d showing 93-100% maximum inhibition of CHIKV replication in cell-based assay having EC90 of 8.76-9.57 μg/mL. Intensive molecular modeling studies including covalent docking, lowest unoccupied molecular orbital energies, and the atomic condensed Fukui functions calculations strongly suggested the covalent binding of peptidomimetics 3a, 4b, and 5d to CHIKV nsP2 protease leading to permanent enzyme inactivation via Michael adduct formation between α/β-unsaturated ketone functionality in our designed peptidomimetics and active site catalytic cysteine1013. Furthermore, small molecular weight peptidomimetics 3a and 4b satisfied the Lipinski rule of five for drug-likeness and showed promising intestinal absorption and aqueous solubility via computational admet studies making them promising hits for further optimization.

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Assessment of new anti-HER2 ligands using combined docking, QM/MM scoring and MD simulation

Cited by 19 publications

References 31 publications

Computational analyses of curcuminoid analogs against kinase domain of HER2

Computational analyses of curcuminoid analogs against kinase domain of HER2

Human PD-1 binds differently to its human ligands: A comprehensive modeling study

Discovery of Novel Peptidomimetics as Irreversible CHIKV NsP2 Protease Inhibitors Using Quantum Mechanical‐Based Ligand Descriptors

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