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

Ali HI, Nagamatsu T, Akaho E - Bioinformation (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Structures of the compounds tested for the tyrosine kinase inhibition by computer docking.
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Related In: Results  -  Collection


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Figure 1: Structures of the compounds tested for the tyrosine kinase inhibition by computer docking.

Mentions: The compounds investigated in this study include 2, 3, 4-trisubstitutred-1, 2-dihydropyrrolo[1, 2-a][1, 3, 5]triazin derivatives Ia-k, 4-(3, 5-di-tertbutylphenylcarbamoyl)-2-amino benzoic acid, or 2-nitro benzoic acid, or their methylester analogs IIa-d, benzopyrido, benzopyrimido, or benzopiprazino[1, 4]dioxin-2-ol IIIa-c and dipyrido[1, 4] dioxin-2-ol analogs IIId-g, 2-substituted-(6-fluoro-3, 4-dihydro-4-substituted phenoxypyrido[3, 4-d]pyrimidin-2-yl) derivatives IVa-d, tyrosine containing di- or tripeptides Va-f, acetylated tyrosine containing tetrapeptides analogs Vg-m, deazapteridine-steroid hybrid compounds VIa-d, as a new class of the hybrid compounds possessing 5-deazapteridine and steroid in the same ring system, synthesized by condensation of 6-(monosubstituted amino) uracils or 6-(monosubstituted amino)-2-phenylpyrimidin-4(3H)-ones with 2-hydroxy-methylene androstanolone or 2-hydroxymethyl- enetestosterone under heating in the presence of p-toluenesulfonic acid monohydrate.12 5-deazaflavin derivatives including: 2-deoxo-2-phenyl-5-deazaflavins VIIah,13,142-deoxo-2-piperidino-5-deazaflavin VIIi,15 2-deoxo-2-morpholino-5-deazaflavin VIIj,15 new 2-deoxo-2-phenylflavins VIIm-o, computationally newly designed 2-deoxo-2-glycino, 2-tyrosino, and 2-histidi- no-N10-methylflavin-N-oxides VIIp-r, respectively, new 5-deazaflavin derivatives VIIIa-c, N3-methyl -5-(monosubstituted alkylamino)-5-deazaflavin derivatives VIIId-g, and 14 computationally designed pyridodipyrimidines IXa-f, 14 bis-(5-deazaflavin-10-yl) alkanes Xa,14 and Xb. Additional compounds were obtained from Sumisho data base (Figure 1). Those include abacavir, PB-01547328, PB-99211665, F0007-0958, OSSK-633719, OSSK-692604, 831, PB-00623451, and compound 1505335.


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

Ali HI, Nagamatsu T, Akaho E - Bioinformation (2011)

Structures of the compounds tested for the tyrosine kinase inhibition by computer docking.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044423&req=5

Figure 1: Structures of the compounds tested for the tyrosine kinase inhibition by computer docking.
Mentions: The compounds investigated in this study include 2, 3, 4-trisubstitutred-1, 2-dihydropyrrolo[1, 2-a][1, 3, 5]triazin derivatives Ia-k, 4-(3, 5-di-tertbutylphenylcarbamoyl)-2-amino benzoic acid, or 2-nitro benzoic acid, or their methylester analogs IIa-d, benzopyrido, benzopyrimido, or benzopiprazino[1, 4]dioxin-2-ol IIIa-c and dipyrido[1, 4] dioxin-2-ol analogs IIId-g, 2-substituted-(6-fluoro-3, 4-dihydro-4-substituted phenoxypyrido[3, 4-d]pyrimidin-2-yl) derivatives IVa-d, tyrosine containing di- or tripeptides Va-f, acetylated tyrosine containing tetrapeptides analogs Vg-m, deazapteridine-steroid hybrid compounds VIa-d, as a new class of the hybrid compounds possessing 5-deazapteridine and steroid in the same ring system, synthesized by condensation of 6-(monosubstituted amino) uracils or 6-(monosubstituted amino)-2-phenylpyrimidin-4(3H)-ones with 2-hydroxy-methylene androstanolone or 2-hydroxymethyl- enetestosterone under heating in the presence of p-toluenesulfonic acid monohydrate.12 5-deazaflavin derivatives including: 2-deoxo-2-phenyl-5-deazaflavins VIIah,13,142-deoxo-2-piperidino-5-deazaflavin VIIi,15 2-deoxo-2-morpholino-5-deazaflavin VIIj,15 new 2-deoxo-2-phenylflavins VIIm-o, computationally newly designed 2-deoxo-2-glycino, 2-tyrosino, and 2-histidi- no-N10-methylflavin-N-oxides VIIp-r, respectively, new 5-deazaflavin derivatives VIIIa-c, N3-methyl -5-(monosubstituted alkylamino)-5-deazaflavin derivatives VIIId-g, and 14 computationally designed pyridodipyrimidines IXa-f, 14 bis-(5-deazaflavin-10-yl) alkanes Xa,14 and Xb. Additional compounds were obtained from Sumisho data base (Figure 1). Those include abacavir, PB-01547328, PB-99211665, F0007-0958, OSSK-633719, OSSK-692604, 831, PB-00623451, and compound 1505335.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

No MeSH data available.