Title

Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors 

Authors

Hamed Ismail Ali¹, Tomofumi Nagamatsu², Eiichi Akaho³*

Affiliation

¹Department of Pharmaceutical Chemistry, Helwan university, Helwan, Egypt; ²Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan; ³Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3, Minatojima, Chuo-ku, Kobe 650-8586, Japan 

Email

akaho@pharm.kobegakuin.ac.jp; *Corresponding author  

+81 78 974 4845

+81 78 974 4845

Article Type

Hypothesis

Date

Received January 04, 2011; Accepted January 06, 2011; Published February 07, 2011
 

Different classes of compounds were investigated for their binding affinities into different protein tyrosine kinases (PTKs) employing a novel flexible ligand docking approach by using AutoDock 3.05 and 4. These compounds include many flavin analogs, which were developed in our group with varying degrees of cytotoxic activity (comparable or moderately superior to cisplatin and ara-c), and database selected analogs. They were docked onto twelve different families of PTKs retrieved from the Protein Data Bank. These proteins are representatives of plausible models of interactions with chemotherapeutic agents. A comparative study of the intact co-crystallized ligands of various types of PTKs was carried out. Results revealed that the new class of 5-deazapteridine and steroid hybrid compounds VIa,b, and d, and the vertical-type bispyridodipyrimidine with n-hexyl chain junction between its N-10 and N-10 atoms Xa, exhibited non-selective PTK binding capacities, with the lowest ?Gb. On the other hand, 2-amino benzoic acid analog IIa, phenoxypyrido [3, 4-d]pyrimidine derivative IVc, tyrosine containing tripeptide Vd, and the one from Sumisho data base 831 are proposed to have selective PTK binding affinities to certain classes of tyrosine kinases, namely, HGFR (c-met), ZAP-70, insulin receptor kinase, EGFR, respectively. All These compounds of highest affinities were docked within the binding sites of PTKs with reasonable RMSD and 1-5 hydrogen bonds.  

Citation

Ali & Akaho. Bioinformation 5(9): 368-374 (2011)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.