Abstract
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.
Highlights
In 2009, two kinase inhibitors were approved for the treatment of cancer; and another for the treatment of renal cell carcinoma [1]
It was reported that docking programs are able to predict experimental poses with deviation average from 1.5 to 2.0 Å root mean square deviation (RMSD) [5]
We investigated the AutoDock binding affinities of various structures for their potential protein tyrosine inhibitory activities, including: 2, 3, 4
Summary
In 2009, two kinase inhibitors were approved for the treatment of cancer; and another for the treatment of renal cell carcinoma [1]. Protein-tyrosine kinases (PTKs) play an important role in the control of most fundamental cellular processes including the cell cycle, cell migration, cell metabolism, and cell survival, as well as cell proliferation and differentiation [2]. Docking of the molecules into their respective 3D macromolecular targets is a widely used method for lead optimization [3]. Docking programs find their most important applications in virtual database screening approaches in which hundreds of thousands of molecules are docked into the binding pocket to identify plausible binders [4]. Structure-based drug design methods utilize knowledge of the three-dimensional structure of a receptor complexed with a lead molecule in an attempt to optimize the bound ligand or a series of congeneric molecules. Using a model with a given structure, a medicinal chemist can compute an activity of a molecule [7]
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