Structural insights into the polypharmacological activity of quercetin on serine/threonine kinases

Figures & data

Figure 1 Structure of (A) quercetin and (B) isoquercitrin.

Figure 2 Structure of serine/threonine kinases.

Notes: The protein is shown in cartoon representation and colored in rainbow colors with violet at the N-terminus and red at the C-terminus of the structure. The N- and C-lobes with the connecting hinge region are indicated. The catalytic loop, activation loop, glycine-rich loop, C-helix, and the DFG motif are labeled. The Chk1 protein structure (PDB ID: 1ZYS) belonging to the CaMK family of serine/threonine protein kinases was used to generate this image.
Abbreviations: C-lobe, C-terminal lobe; DFG, Asp–Phe–Gly; N-lobe, N-terminal lobe; PDB, Protein Data Bank.

Table 1 Proteins and PDB IDs of structures used in this study

Groups	Protein	PDB ID	Resolution (Å)
AGC	Akt1	3MVH	2.01
	Akt2	2UW9	2.10
	Aurora kinase	4J8M	1.85
	RSK2	4NW5	1.94
CaMK	Chk1	1ZYS	1.70
CMGC	CDK2	4EK4	1.55
	ERK2	4ZZN	1.33
	p38α	4R3C	2.06
	JNK1	4QTD	1.50
	GSK3B	1J1B	1.80
	CLK1	1Z57	1.70
STE	MEK1	3VVH	2.00
	PAK4	2Q0N	1.75
	Plk1	2RKU	1.95
TKL	B-Raf	5CSW	2.66

Abbreviation: PDB, Protein Data Bank.

Table 2 Interactions of quercetin, isoquercitrin, and selected inhibitors with serine/threonine kinases

Group	Target	PDB ID	Ligand	Hydrogen bonds	Hydrophobic interactions	π–π or cation–π interactions	XP GlideScore (kcal/mol)	MM–GBSA binding energy (kcal/mol)
AGC	Akt1	3MVH	Quercetin	Glu228, Ala230, Asp292	Leu156, Val164, Ala177, Met227, Tyr229, Met281, Phe438, Phe442		−9.79	−64.71
			Isoquercitrin	Glu228, Asp292	Leu156, Val164, Ala177, Met227, Tyr229, Ala230, Met281, Phe438, Phe442		−9.86	−69.79
			GSK690693	Asp439	Leu156, Phe161, Val164, Ala177, Leu181, Phe236, Phe237, Met281, Tyr437, Phe438	Phe442	−5.42	−64.09
	Akt2	2UW9	Quercetin	Lys160, Glu230, Ala232, Thr292, Asp293	Leu158, Val166, Ala179, Met229, Tyr231, Met282, Phe439, Phe443		−9.97	−63.45
			Isoquercitrin	Lys160, Glu236, Lys277, Asp293, Asp440	Leu158, Val166, Ala179, Met229, Phe238, Phe239, Met282, Phe439, Phe443		−10.91	−68.70
			GSK690693	Leu158, Thr213, Asn280, Asp440	Val166, Ala179, Met229, Tyr231, Ala232, Phe239, Met282, Tyr438, Phe439, Phe443		−7.10	−73.94
	Aurora	4J8M	Quercetin	Leu139, Glu211, Ala213, Asp274	Val147, Ala160, Leu194, Leu210, Tyr212, Leu263, Ala273		−8.16	−62.39
			Isoquercitrin	Glu211, Ala213, Asp274	Leu139, Val147, Ala160, Leu194, Leu210, Tyr212, Leu263, Ala273, Ala281, Pro282		−10.22	−71.01
			AT9283	Ala213, Thr217	Leu139, Val147, Ala160, Leu194, Leu210, Tyr212, Pro214, Tyr219, Leu263, Ala273, Ala281		−6.71	−70.34
	RSK2	4NW5	Quercetin	Leu74, Leu150, Asp211	Val82, Leu147, Ala98, Phe149, Leu200		−10.14	−69.17
			Isoquercitrin	Gln76, Asp148, Leu150, Asn198	Leu74, Val82, Ala98, Phe149, Leu200, Val131, Leu147		−12.44	−88.84
			BI-D1870	Lys72, Leu150	Leu74, Val82, Ala98, Leu200, Val131, Leu147, Phe149		−8.41	−78.42
CaMK	Chk1	1ZYS	Quercetin	Lys38, Glu85, Cys87, Asp148	Leu15, Tyr20, Val23, Ala36, Val68, Leu84, Tyr86, Leu137		−8.38	−63.43
			Isoquercitrin	Glu17, Cys87, Asn135, Asp148	Leu15, Tyr20, Val23, Ala36, Val68, Leu84, Tyr86, Leu137, Phe149		−11.67	−79.53
			AZD7762	Glu85, Cys87, Glu91	Leu15, Tyr20, Val23, Ala36, Leu84, Val68, Tyr86, Leu137		−7.15	−83.52
CMGC	CDK2	4EK4	Quercetin	Leu83, Gln131, Asp145	Ile10, Val18, Ala31, Phe82, Leu134, Ala144		−9.33	−64.14
			Isoquercitrin	Thr14, Lys33, Leu83, Gln131, Asp145	Ile10, Val18, Ala31, Leu134		−10.49	−70.09
			Dinaciclib	Lys33, Asp86, Lys89	Ile10, Val18, Ala31, Val64, Phe80, Phe82, Leu83, Leu134, Ala144		−5.57	−75.63
	ERK2	4ZZN	Quercetin	Lys52, Met106, Asp109, Asp165	Ile29, Ala33, Tyr34, Val37, Ala50, Ile82, Leu105, Leu154, Cys164		−6.69	−59.57
			Isoquercitrin	Gln103, Met106, Asp109, Asp165	Ile29, Ala33, Tyr34, Val37, Ala50, Ile82, Leu105, Leu154, Lys164	Lys52	−8.61	−68.49
			SCH772984	Lys52, Asp104, Lys112	Ile29, Ala33, Val37, Ala50, Ile82, Leu105, Tyr111, Met106, Leu154, Lys164		−6.61	−74.69
	p38α	4R3C	Quercetin	Lys53, Met109, Asp112, Asp168	Val30, Val38, Ala51, Ile84, Leu108, Ala111, Leu167, Met179, Tyr182		−6.69	−44.85
			Isoquercitrin	His107, Met109, Asp112, Asp168	Val30, Val38, Ala51, Ile84, Leu108, Leu167, Met179, Tyr182		−9.31	−69.86
			Doramapimod	Asp168	Val30, Ala34, Tyr35, Val38, Ala51, Leu75, Ile84, Leu108, Met109, Ala111, Ala157, Leu167, Phe169		−4.87	−79.74
	JNK1	4QTD	Quercetin	Ala36, Lys55, Glu73, Asp151, Asn156, Leu168	Val40, Ile86, Met108, Leu172, Val187		−8.20	−45.53
			Isoquercitrin	Ala36, Arg69, Asp151, Ser155, Asn156, Leu168	Val40, Ile86, Met108, Phe170, Leu172, Val186, Val187	Arg69	−10.60	−50.23
			AS601245	Lys55, Met111	Ile32, Ala36, Val40, Ala53, Ile86, Met108, Leu110, Val158, Leu168		−9.03	−81.19
	GSK3B	1J1B	Quercetin	Lys85, Val135, Gln185, Asp200	Ile62, Val70, Ala83, Val110, Leu132, Tyr134, Leu188, Cys199		−9.29	−55.35
			Isoquercitrin	Ile62, Asn64, Lys85, Val135, Arg141, Gln185, Asp200	Val70, Val110, Leu132, Tyr134, Pro136, Tyr140, Leu188, Cys199, Phe201	Arg141	−10.44	−62.59
			CHIR-99021	Ile62, Asn64	Val70, Ala83, Leu108, Val110, Leu132, Tyr134, Val135, Pro136, Leu188, Cys199	Lys85, Arg141	−5.94	−67.09
	CLK1	1Z57	Quercetin	Leu167, Lys191, Asp250, Asp325	Phe172, Val175, Ala189, Val225, Phe241, Leu243, Leu244, Leu295, Val324		−8.99	−62.96
			Isoquercitrin	Gly245, Asp250, Asp325	Leu167, Phe172, Val175, Ala189, Val225, Phe241, Leu243, Leu244, Leu246, Tyr249 Leu295, Val324		−10.53	−73.19
STE	MEK1	3VVH	Quercetin	Leu74, Glu144, Met146, Asn195, Asp208	Ala76, Val82, Ala95, Val127, Met143, Leu197, Cys207		−9.97	−64.99
			Isoquercitrin	Met146, Ser194, Asp152, Asp208	Leu74, Ala76, Val82, Ala95, Met143, Leu197, Cys207		−9.65	−68.12
	PAK4	2Q0N	Quercetin	Glu329, Glu396, Leu398, Asp458	Ile327, Val335, Ala348, Val379, Met395, Phe397, Leu447		−10.03	−58.22
			Isoquercitrin	Glu396, Leu398, Ala402, Asp458	Ile327, Val335, Ala348, Val379, Met395, Phe397, Leu447		−9.86	−60.47
	Plk1	2RKU	Quercetin	Leu59, Lys82, Glu131, Cys133, Asp194	Cys67, Ala80, Val114, Leu130, Leu132, Phe183, Phe195		−10.89	−62.84
			Isoquercitrin	Leu59, Lys82, Glu140, Cys133, Asp194	Cys67, Ala80, Val114, Leu130, Leu132, Leu139	Phe183	−11.26	−74.86
TKL	B-Raf	5CSW	Quercetin	Cys532, Asp594, Phe595	Ile463, Phe468, Val471, Ala481, Leu505, Leu514, Ile527, Trp531, Phe583		−9.48	−60.46
			Isoquercitrin	Cys532, Gly534, Ser536, Asn580, Phe583, Asp594	Leu514, Ile463, Val471, Ala481, Trp531, Tyr538		−11.07	−67.72

Abbreviations: MM–GBSA, molecular mechanics–generalized Born surface area; PDB, Protein Data Bank; XP, extra precision.

Figure 3 Docked pose and hydrogen bond interactions of quercetin and isoquercitrin with serine/threonine protein kinases.

Notes: One protein has been chosen from each group. (A) Quercetin in Akt1 (AGC group), (B) isoquercitrin in Akt1, (C) quercetin in Chk1 (CaMK group), (D) isoquercitrin in Chk1, (E) quercetin in CDK2 (CMGC group), (F) isoquercitrin in CDK2, (G) quercetin in MEK1 (STE group), (H) isoquercitrin in MEK1, (I) quercetin in B-Raf (TKL group), (J) isoquercitrin in B-Raf. The protein is shown in light-blue cartoon representation, interacting residues are shown in stick representation, and the docked ligand is represented as black sticks.
Abbreviation: PDB, Protein Data Bank.

Figure S1 Docked pose and hydrogen bond interactions of quercetin and isoquercitrin with AGC family serine/threonine kinases.

Notes: (A) Quercetin in Akt2, (B) isoquercitrin in Akt2, (C) quercetin in aurora kinase, (D) isoquercitrin in aurora kinase, (E) quercetin in RSK2, (F) isoquercitrin in RSK2. The protein is shown in light-blue cartoon representation, interacting residues are shown in stick representation, and the docked ligand is represented as black sticks.
Abbreviation: PDB, Protein Data Bank.

Figure S2 Docked pose and hydrogen bond interactions of quercetin and isoquercitrin with CMGC family serine/threonine kinases.

Notes: (A) Quercetin in ERK2, (B) isoquercitrin in ERK2, (C) quercetin in p38α, (D) isoquercitrin in p38α, (E) quercetin in JNK1, (F) isoquercitrin in JNK1, (G) quercetin in GSK3B, (H) isoquercitrin in GSK3B, (I) quercetin in CLK1, (J) isoquercitrin in CLK1. The protein is shown in light-blue cartoon representation, interacting residues are shown in stick representation, and the docked ligand is represented as black sticks.
Abbreviation: PDB, Protein Data Bank.

Figure S3 Docked pose and hydrogen bond interactions of quercetin and isoquercitrin with STE family serine/threonine kinases.

Notes: (A) Quercetin in PAK4, (B) isoquercitrin in PAK4, (C) quercetin in Plk1, (D) isoquercitrin in Plk1. The protein is shown in light-blue cartoon representation, interacting residues are shown in stick representation, and the docked ligand is represented as black sticks.
Abbreviation: PDB, Protein Data Bank.