Browsing by Author "Abouzid K.A."

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    Assessment of new anti-HER2 ligands using combined docking, QM/MM scoring and MD simulation
    (2013) Ahmed M.; Sadek M.M.; Serrya R.A.; Kafafy A.-H.N.; Abouzid K.A.; Wang F.; EChemistry Laboratory; Faculty of Life and Social Sciences; Swinburne University of Technology; Melbourne; VIC 3122; Australia; Pharmaceutical Organic Chemistry; Faculty of Pharmacy; MSA University; Egypt; Pharmaceutical Chemistry Department; Faculty of Pharmacy; Ain Shams University; Cairo 11566; Egypt; Pharmaceutical Organic Chemistry Department; Faculty of Pharmacy; Assiut University; Egypt
    In the development of new anti-cancer drugs to tackle the problem of resistance to current chemotherapeutic agents, a new series of anti-HER2 (human epidermal growth factor receptors 2) agents has been synthesized and investigated using different computational methods. Although non-selective, the most active inhibitor in the new series shows higher activity toward HER2 than EGFR. The induced fit docking protocol (IFD) is performed to find possible binding poses of the new inhibitors in the active site of the HER2 receptor. Molecular dynamic simulations of the inhibitor-protein complexes for the two most active compounds from the new series are carried out. Simulations stability is checked using different stability parameters. Different scoring functions are employed. � 2012 Elsevier Inc.
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    In silico design: Extended molecular dynamic simulations of a new series of dually acting inhibitors against EGFR and HER2
    (Elsevier Inc., 2013) Ahmed M.; Sadek M.M.; Abouzid K.A.; Wang F.; Chemistry Laboratory; Faculty of Life and Social Sciences; Swinburne University of Technology; Hawthorn; Melbourne; VIC 3122; Australia; Pharmaceutical Organic Chemistry; Faculty of Pharmacy; MSA University; Egypt; Pharmaceutical Chemistry Department; Faculty of Pharmacy; Ain Shams University; Cairo 11566; Egypt
    Based on the hit structures that have been identified in our previous studies against EGFR and HER2, new potential inhibitors that share the same scaffold of the hit structures are designed and screened in silico. Insights into understanding the potential inhibitory effect of the new inhibitors against both EGFR and HER2 receptors is obtained using extended molecular dynamics (MD) simulations and different scoring techniques. The binding mechanisms and dynamics are detailed with respect to two approved inhibitors against EGFR (lapatinib) and HER2 (SYR127063). The best scoring inhibitor (T9) is chosen for additional in silico investigation against both the wild-type and T790M mutant strain of EGFR and the wild-type HER2. The results reveal that certain substitution patterns increase the stability and assure stronger binding and higher H-bond occupancy of the conserved water molecule that is commonly observed with kinase crystal structures. Furthermore, the new inhibitor (T9) forms stable interactions with the mutant strain as a direct consequence of the enhanced ability to form additional hydrogen bonding interactions with binding site residues. 2013 Elsevier Ltd. All rights reserved.