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Combination of pharmacophore hypothesis, genetic function approximation model, and molecular docking to identify novel inhibitors of S6K1.

Zhang H, Xiang ML, Liang JY, Zeng T, Zhang XN, Zhang J, Yang SY - Mol. Divers. (2013)

Bottom Line: Discovery of S6K1 inhibitors has thus attracted much attention in recent years.The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors.Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test.

View Article: PubMed Central - PubMed

Affiliation: College of Life Science, Northwest Normal University, Lanzhou , 730070, Gansu, People's Republic of China, zhanghui123gansu@163.com.

ABSTRACT
S6K1 has emerged as a potential target for the treatment for obesity, type II diabetes and cancer diseases. Discovery of S6K1 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening method that involves pharmacophore hypothesis, genetic function approximation (GFA) model, and molecular docking technology has been used to discover S6K1 inhibitors especially with novel scaffolds. The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors. Then, the molecular docking method was carried out to re-filter these screened compounds. Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test.

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Related in: MedlinePlus

(A) One of the final hit compounds, AG227/42189090, mapped with the pharmacophore model Hypo1. (B) The binding mode of AG227/42189090 with S6K1 (dashed lines represent hydrogen bonds)
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Fig5: (A) One of the final hit compounds, AG227/42189090, mapped with the pharmacophore model Hypo1. (B) The binding mode of AG227/42189090 with S6K1 (dashed lines represent hydrogen bonds)

Mentions: In order to discover S6K1 inhibitors with new scaffolds, we further clustered the 215 compounds into ten classes, and selected 2–7 compounds from each class. Finally, 60 potential active compounds were carefully selected (see Table S1) and have been handed over to other research group to complete the follow-up compound synthesis (or purchase) and activity test, whose results will be reported in the near future. For these promising inhibitors selected by the combined screening method, the representative structures of which mainly include hydrophobic moiety, ring-aromatic moiety, hydrogen bond donor feature and hydrogen bond acceptor feature. Furthermore, the hydrophobic moiety and ring-aromatic moiety of inhibitors situate at hydrophobic pocket of the S6K1 protein. The hydrogen bond donor feature and hydrogen bond acceptor feature of inhibitors form hydrogen-bonds to the sidechains of S6K1. Moreover, all the selected inhibitors are predicted to have good interactions with the active site of residues of Leu-175, Glu-179, and Met-225. For example, Fig. 5 shows the pharmacophore mapping and binding mode of one of the best retrieved compounds. As can be seen from the Fig. 5A, the hit compound AG227/42189090 (4-[3-(4-chlorobenzoyl)-2-(2-fluorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]butanoic acid) is mapped very well with these features of the Hypo1. The binding pose of AG227/42189090 in the ATP binding pocket is also shown in Fig. 5B. The 2-fluorophenyl moiety (hydrophobic feature) and 4-chlorobenzoyl group (ring-aromatic feature) make many favorable van der Waals contacts with the backbone and side chains of residues. The hydrogen bond acceptor feature in Hypo1 corresponds to the hydrogen bond interaction formed between the carboxyl pyrrol of the AG227/42189090 and amide nitrogen of Leu-175 in the linker region. The hydrogen bond donor feature in Hypo1 corresponds to the hydrogen bond interaction formed between the 4-hydroxy of AG227/42189090 and carboxyl of Leu-175. The butanoic acid group is directed toward the solvent accessible region. The observed van der Waals interactions and characteristic polar contacts are consistent with the Ye et al [17] provided a possible pharmacophore model of S6K1 inhibitors.Fig. 5


Combination of pharmacophore hypothesis, genetic function approximation model, and molecular docking to identify novel inhibitors of S6K1.

Zhang H, Xiang ML, Liang JY, Zeng T, Zhang XN, Zhang J, Yang SY - Mol. Divers. (2013)

(A) One of the final hit compounds, AG227/42189090, mapped with the pharmacophore model Hypo1. (B) The binding mode of AG227/42189090 with S6K1 (dashed lines represent hydrogen bonds)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824193&req=5

Fig5: (A) One of the final hit compounds, AG227/42189090, mapped with the pharmacophore model Hypo1. (B) The binding mode of AG227/42189090 with S6K1 (dashed lines represent hydrogen bonds)
Mentions: In order to discover S6K1 inhibitors with new scaffolds, we further clustered the 215 compounds into ten classes, and selected 2–7 compounds from each class. Finally, 60 potential active compounds were carefully selected (see Table S1) and have been handed over to other research group to complete the follow-up compound synthesis (or purchase) and activity test, whose results will be reported in the near future. For these promising inhibitors selected by the combined screening method, the representative structures of which mainly include hydrophobic moiety, ring-aromatic moiety, hydrogen bond donor feature and hydrogen bond acceptor feature. Furthermore, the hydrophobic moiety and ring-aromatic moiety of inhibitors situate at hydrophobic pocket of the S6K1 protein. The hydrogen bond donor feature and hydrogen bond acceptor feature of inhibitors form hydrogen-bonds to the sidechains of S6K1. Moreover, all the selected inhibitors are predicted to have good interactions with the active site of residues of Leu-175, Glu-179, and Met-225. For example, Fig. 5 shows the pharmacophore mapping and binding mode of one of the best retrieved compounds. As can be seen from the Fig. 5A, the hit compound AG227/42189090 (4-[3-(4-chlorobenzoyl)-2-(2-fluorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]butanoic acid) is mapped very well with these features of the Hypo1. The binding pose of AG227/42189090 in the ATP binding pocket is also shown in Fig. 5B. The 2-fluorophenyl moiety (hydrophobic feature) and 4-chlorobenzoyl group (ring-aromatic feature) make many favorable van der Waals contacts with the backbone and side chains of residues. The hydrogen bond acceptor feature in Hypo1 corresponds to the hydrogen bond interaction formed between the carboxyl pyrrol of the AG227/42189090 and amide nitrogen of Leu-175 in the linker region. The hydrogen bond donor feature in Hypo1 corresponds to the hydrogen bond interaction formed between the 4-hydroxy of AG227/42189090 and carboxyl of Leu-175. The butanoic acid group is directed toward the solvent accessible region. The observed van der Waals interactions and characteristic polar contacts are consistent with the Ye et al [17] provided a possible pharmacophore model of S6K1 inhibitors.Fig. 5

Bottom Line: Discovery of S6K1 inhibitors has thus attracted much attention in recent years.The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors.Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test.

View Article: PubMed Central - PubMed

Affiliation: College of Life Science, Northwest Normal University, Lanzhou , 730070, Gansu, People's Republic of China, zhanghui123gansu@163.com.

ABSTRACT
S6K1 has emerged as a potential target for the treatment for obesity, type II diabetes and cancer diseases. Discovery of S6K1 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening method that involves pharmacophore hypothesis, genetic function approximation (GFA) model, and molecular docking technology has been used to discover S6K1 inhibitors especially with novel scaffolds. The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors. Then, the molecular docking method was carried out to re-filter these screened compounds. Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test.

Show MeSH
Related in: MedlinePlus