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Deep analysis of N-cadherin/ADH-1 interaction: a computational survey
Authors:Mahboobeh Eslami  Navid Nezafat  Sahar Khajeh  Zohreh Mostafavi-Pour  Samaneh Bagheri Novir  Manica Negahdaripour
Affiliation:1. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;2. Biochemistry Department, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran;3. Recombinant Protein Lab, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran;4. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran;5. Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
Abstract:Due to the considerable role of N-cadherin in cancer metastasis, tumor growth, and progression, inhibition of this protein has been highly regarded in recent years. Although ADH-1 has been known as an appropriate inhibitor of N-cadherin in clinical trials, its chemical nature and binding mode with N-cadherin have not been precisely specified yet. Accordingly, in this study, quantum mechanics calculations were used to investigate the chemical nature of ADH-1. These calculations clarify the molecular properties of ADH-1 and determine its reactive sites. Based on the results, the oxygen atoms are suitable for electrophilic reactivity, while the hydrogen atoms that are connected to nitrogen atoms are the favorite sites for nucleophilic reactivity. The higher electronegativity of the oxygen atoms makes them the most reactive portions in this molecule. Molecular docking and molecular dynamics (MD) simulation have also been applied to specify the binding mode of ADH-1 with N-cadherin and determine the important residues of N-cadherin involving in the interaction with ADH-1. Moreover, the verified model by MD simulation has been studied to extract the free energy value and find driving forces. These calculations and molecular electrostatic potential map of ADH-1 indicated that hydrophobic and electrostatic interactions are almost equally involved in the implantation of ADH-1 in the N-cadherin binding site. The presented results not only enable a closer examination of N-cadherin in complex with ADH-1 molecule, but also are very beneficial in designing new inhibitors for N-cadherin and can help to save time and cost in this field.
Keywords:N-cadherin  ADH-1  classical molecular dynamics simulations  quantum mechanics calculations  molecular docking
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