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.

Fig 1. Structures of flavones (1–19) and chalcones (20–37).

Fig 2. Binding modes of the compounds under study into CDK1 binding site.

(A) flavones, compounds 1–19 (B) chalcones with orientation I, compounds 31–37, (C) chalcones with orientation II, compounds 20–30.

Fig 3. Template alignment (TA) for all compounds used for CoMFA and CoMSIA.

Fig 4

Scatter plot of the experimental activities versus predicted activities for the best CoMSIA models using TA (A), DA (B) and DAI (C). (●) training-set predictions, (○) LOO cross-validated predictions, (×) test-set predictions.

Fig 5

CoMSIA contour maps for CDK1 inhibitors deriving from the best models for the TA (A), DA (B) and DAI (C) alignments. Compound 20 is shown inside the fields in (A) and (B), and compound 4 is shown inside the fields in (C). In (B) and (C), the amino acid residues located close to the binding pocket of CDK1 are represented for comparing their position with the position of isopleths derived from the model. Hydrophobic field: yellow isopleths indicate regions where hydrophobic groups favor the activity, and gray isopleths indicate regions where hydrophilic groups favor the activity. HB donor field: cyan isopleths indicate regions where HB donors favor the activity, and purple isopleths indicate regions where HB donors disfavor the activity. Steric field (in C): green isopleths indicates region where bulky groups favor the activity.