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.
Highlights
Flavonoids, natural products found abundantly in vegetables and fruits, are phytonutrients with many positive health benefits for humans [1]
There is no previous information about the binding poses of flavonoids inside CDK1 binding site; the quality of the obtained docking results was evaluated by analyzing the structural elements that typically are found in the complexes between protein kinases (PKs) and inhibitors
It is known that ATP-competitive PK inhibitors generally mimic binding of the adenine of ATP to the hinge region of the PK; it is expected that the studied flavonoids have hydrogen bond (HB) interactions with the hinge region residues
Summary
Flavonoids, natural products found abundantly in vegetables and fruits, are phytonutrients with many positive health benefits for humans [1]. They are famous for their antioxidant and anti-inflammatory health benefits, as well as their contribution of flashy color to the foods we eat; they provide benefits in the prevention of chronic diseases such as diabetes, osteoporosis and cancer caused by free-radical damage [2,3,4,5]. Flavonoids alter PK phosphorylation state to regulate multiple cell signaling pathways. This process has been associated to mechanism for the antioxidant functions of flavonoids, since they can exert their antioxidant properties through binding PKs to regulate the expression of antioxidant enzymes [15,16]
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