Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship

Abstract

In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure–activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities.

Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure–Activity Analysis

“…2) are low-molecular weight, aromatic compounds that are components of fruits, vegetables, and other plant components. It is possible that inhibition of protein kinases by flavonoids contributes to their reported ability to reduce the risks of cardiovascular disease, diabetes and cancer 26–28 . Flavonoids have other targets; they inhibit the structurally-similar phosphatidylinositol 3-kinase-γ (PI3Kγ) 25, 28–29 , and they also interact with unrelated, non-kinase targets, such as mammalian F 1 -ATPase 30 , xanthine oxidase 31 , serine protease 32 and telomeric DNA 33 .…”

Docking and quantitative structure–activity relationship of bi-cyclic heteroaromatic pyridazinone and pyrazolone derivatives as phosphodiesterase 3A (PDE3A) inhibitors

“…These results are in agreement with previous reports where authors found that docking based alignments yield poorer QSAR predictive models since the fluctuations in the positions of common or analogous atoms due to different compounds conformations inside the binding site have a negative influence when generating fields. [ 41 – 43 ] The combination of multiple fields during FQSAR application under the DA scheme did not produce any substantial increase of the statistical performance. The DA- H model produced and with one PLS component.…”

“…Such alignment approach has led to the rigth predictions in previous QSAR investigations. [ 40 , 41 ] Fig 4 displays the resultant molecular alignments. Compounds from sets 2 – 4 have the same spatial arrangement in PPA and PA schemes ( Fig 4A ).…”

Schaftoside Interacts With NlCDK1 Protein: A Mechanism of Rice Resistance to Brown Planthopper, Nilaparvata lugens

“…The ATP binding element GXGXXGXV of NlCDK1 contains 2 phosphate sites Thr14 and Tyr15 ( Figure 9 and Supplementary Figure S5 ), so the binding of schaftoside might affect the interacting of ATP and the regulating proteins upstream, such as wee1 and cdc25. Similarly, some flavonoids, such as chalcones and flavones, have also been reported as potent ATP competitive inhibitor of CDK1 ( Navarro-Retamal and Caballero, 2016 ). Under a situation that schaftoside competed for binding to the phosphate site Thr14 by forming a strong hydrogen bond (O 1 -OG 1 ), the activation of NlCDK1 as a protein kinase should be affected ( Table 2 ).…”

“…Knockdown of CDK1 caused cell death in Drosophila melanogaster ( Björklund et al, 2006 ). Some flavonoids, especifically chalcones and flavones containing nitrogen, have been reported as CDK1 inhibitors ( Navarro-Retamal and Caballero, 2016 ). Therefore, CDK1 in BPH (NlCDK1) might be a potential target of rice flavonoids, and worthy being further studied.…”