3D-QSAR and Surflex Docking Studies of a Series of Alkaline Phosphatase Inhibitors
|
摘要
Alkaline phosphatases(APs) include the placental AP(PLAP), germ cell AP(GCAP), intestinal AP(IAP) and tissue nonspecific AP(TNAP). Over expression of TNAP in smooth muscle cells of kidney and vessels provokes the progress of such serious diseases as end-stage renal disease, idiopathic infantile arterial calcification, ankylosis, osteoarthritis and diabetes. In order to design and optimize the potent TNAP inhibitors, comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) were used to analyze 3D structure-activity relationships(3D-QSAR) of TNAP inhibitors. The 3D-QSAR model(CoMFA with q~2 = 0.521, r~2 = 0.930; CoMSIA with q~2 = 0.529, r~2 = 0.933) had a good predictability. Surflex-dock was used to reveal the binding mode between the inhibitors and TNAP protein. CoMFA, CoMSIA and docking results provide guidance for the discovery of TNAP inhibitors. Finally, eight new compounds as potential TNAP inhibitors were designed.
Alkaline phosphatases(APs) include the placental AP(PLAP), germ cell AP(GCAP), intestinal AP(IAP) and tissue nonspecific AP(TNAP). Over expression of TNAP in smooth muscle cells of kidney and vessels provokes the progress of such serious diseases as end-stage renal disease, idiopathic infantile arterial calcification, ankylosis, osteoarthritis and diabetes. In order to design and optimize the potent TNAP inhibitors, comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) were used to analyze 3D structure-activity relationships(3D-QSAR) of TNAP inhibitors. The 3D-QSAR model(CoMFA with q~2 = 0.521, r~2 = 0.930; CoMSIA with q~2 = 0.529, r~2 = 0.933) had a good predictability. Surflex-dock was used to reveal the binding mode between the inhibitors and TNAP protein. CoMFA, CoMSIA and docking results provide guidance for the discovery of TNAP inhibitors. Finally, eight new compounds as potential TNAP inhibitors were designed.
Alkaline phosphatases(APs) include the placental AP(PLAP), germ cell AP(GCAP), intestinal AP(IAP) and tissue nonspecific AP(TNAP). Over expression of TNAP in smooth muscle cells of kidney and vessels provokes the progress of such serious diseases as end-stage renal disease, idiopathic infantile arterial calcification, ankylosis, osteoarthritis and diabetes. In order to design and optimize the potent TNAP inhibitors, comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) were used to analyze 3D structure-activity relationships(3D-QSAR) of TNAP inhibitors. The 3D-QSAR model(CoMFA with q~2 = 0.521, r~2 = 0.930; CoMSIA with q~2 = 0.529, r~2 = 0.933) had a good predictability. Surflex-dock was used to reveal the binding mode between the inhibitors and TNAP protein. CoMFA, CoMSIA and docking results provide guidance for the discovery of TNAP inhibitors. Finally, eight new compounds as potential TNAP inhibitors were designed.
引文
(1)Samuels-Reid,J.;Lawrence,B.;Millin,C.;Cope,J.Pediatric devices and adverse events from A to Z:understanding the benefits and risks from a US FDA perspective.Expert.Rev.Med.Devic.2012,9,275-282.
(2)Weinreb,M.;Shinar,D.;Rodan,G.A.Different pattern of alkaline phosphatase,osteopontin,and osteocalcin expression in developing rat bone visualized by in situ hybridization.J.Bone Miner.Res.2010,5,831-842.
(3)Sánchez,D.M.F.;Martínez-Augustin,O.;González,R.;Ballester,I.;Nieto,A.;Gálvez,J.;Zarzuelo,A.Induction of alkaline phosphatase in the inflamed intestine:a novel pharmacological target for inflammatory bowel disease.Biochem.Pharmacol.2004,68,2317-2326.
(4)Prouillet,C.;Mazière,J.C.;Mazière,C.;Wattel,A.;Brazier,M.;Kamel,S.Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway.Biochem.Pharmacol.2004,67,1307-1313.
(5)Ding,Y.A.;Lin,Y.;Shu,M.;Wang,Y.Q.;Wang,L.;Cheng,X.M.;Lin,Z.H.Quantitative structure-activity relationship model for prediction of protein-peptide interaction binding affinities between human amphiphysin-1 SH3 domains and their peptide ligands.Int.J.Pept.Res.Ther.2011,17,75-79.
(6)Chang,Z.C.;Wang,R.;Ding,X.L.;An,C.H.;Hu,Y.;Wang,Y.Q.;Shu,M.;Lin,Z.H.3D-QSAR Modeling,surflex docking and reverse docking studies of diketo-acid derivatives as potent integrase/rnase H inhibitors.Lat.Am.J.Pharm.2016,35,895-904.
(7)An,C.H.;Shu,M.;Zai,X.L.;Zhang,B.N.;Li,J.;Chang,Z.C.;Hu,Y.;Lin,Z.H.Combined 3D-QSAR,pharmacophore and docking studies on benzene-sulfonamide derivatives as potent 12-lipoxygenase inhibitors.Lett.Drug.Des.Discov.2017,14,74-82.
(8)John,E.B.Sybyl.Molecular Modeling System Version7.2.TriposInc,St Louis MO,USA 2007.
(9)Chen,G.H.;Xia,Z.N.;Lu,Y.;Liao,L.M.;Shu,M.;Sun,J.Y.;Li,Z.L.A vector of molecular electronegative distance for chiral compounds(Vmedc)and its applications to codification of central chirality.Acta Chim.Sinica 2008,66,2052-2058.
(10)Yang,L.;Shu,M.;Ma,K.W.;Mei,H.;Jiang,Y.J.;Li,Z.L.ST-scale as a novel amino acid descriptor and its application in QSAM of peptides and analogues.Amino.Acids 2010,38,805-816.
(11)Li,A.;Zhang,X.X.;Shu,M.;Wu,M.J.;Wang,J.;Zhang,J.Y.;Wang,R.;Li,P.;Wang,Y.T.Arctigenin suppresses renal interstitial fibrosis in a rat model of obstructive nephropathy.Phytomedicine 2017,30,28-41.
(12)Wang.J.L.;Cheng,L.P.;Wang,T.C.;Deng,W.;Wu,F.H.Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR,molecular docking,and dynamics simulation techniques.J.Mol.Graph.Model.2017,72,178-186.
(13)Shu,M.;Zhang,Y.R.;Tian,F.F.;Yang,L.;Lin,Z.H.Molecular docking and 3D-QSAR research of biphenyl carboxylic acid MMP-3 inhibitors.Chin.J.Struc.Chem.2012,31,443-451.
(14)Zhang,H.X.;Li,Y.;Wang,X.;Xiao,Z.T.;Wang,Y.H.Insight into the structural requirements of benzothiadiazine scaffold-based derivatives as hepatitis C virus NS5B polymerase inhibitors using 3D-QSAR,molecular docking and molecular dynamics.Curr.Med.Chem.2011,18,4019-4028.
(15)Yu,R.;Wang,J.;Wang,R.;Lin,Y.;Hu,Y.;Wang,Y.Q.;Shu,M.;Lin,Z.H.Combined pharmacophore modeling,3D-QSAR,homology modeling and docking studies on CYP11B1 inhibitors.Molecules 2015,20,1014-1030.
(2)Weinreb,M.;Shinar,D.;Rodan,G.A.Different pattern of alkaline phosphatase,osteopontin,and osteocalcin expression in developing rat bone visualized by in situ hybridization.J.Bone Miner.Res.2010,5,831-842.
(3)Sánchez,D.M.F.;Martínez-Augustin,O.;González,R.;Ballester,I.;Nieto,A.;Gálvez,J.;Zarzuelo,A.Induction of alkaline phosphatase in the inflamed intestine:a novel pharmacological target for inflammatory bowel disease.Biochem.Pharmacol.2004,68,2317-2326.
(4)Prouillet,C.;Mazière,J.C.;Mazière,C.;Wattel,A.;Brazier,M.;Kamel,S.Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway.Biochem.Pharmacol.2004,67,1307-1313.
(5)Ding,Y.A.;Lin,Y.;Shu,M.;Wang,Y.Q.;Wang,L.;Cheng,X.M.;Lin,Z.H.Quantitative structure-activity relationship model for prediction of protein-peptide interaction binding affinities between human amphiphysin-1 SH3 domains and their peptide ligands.Int.J.Pept.Res.Ther.2011,17,75-79.
(6)Chang,Z.C.;Wang,R.;Ding,X.L.;An,C.H.;Hu,Y.;Wang,Y.Q.;Shu,M.;Lin,Z.H.3D-QSAR Modeling,surflex docking and reverse docking studies of diketo-acid derivatives as potent integrase/rnase H inhibitors.Lat.Am.J.Pharm.2016,35,895-904.
(7)An,C.H.;Shu,M.;Zai,X.L.;Zhang,B.N.;Li,J.;Chang,Z.C.;Hu,Y.;Lin,Z.H.Combined 3D-QSAR,pharmacophore and docking studies on benzene-sulfonamide derivatives as potent 12-lipoxygenase inhibitors.Lett.Drug.Des.Discov.2017,14,74-82.
(8)John,E.B.Sybyl.Molecular Modeling System Version7.2.TriposInc,St Louis MO,USA 2007.
(9)Chen,G.H.;Xia,Z.N.;Lu,Y.;Liao,L.M.;Shu,M.;Sun,J.Y.;Li,Z.L.A vector of molecular electronegative distance for chiral compounds(Vmedc)and its applications to codification of central chirality.Acta Chim.Sinica 2008,66,2052-2058.
(10)Yang,L.;Shu,M.;Ma,K.W.;Mei,H.;Jiang,Y.J.;Li,Z.L.ST-scale as a novel amino acid descriptor and its application in QSAM of peptides and analogues.Amino.Acids 2010,38,805-816.
(11)Li,A.;Zhang,X.X.;Shu,M.;Wu,M.J.;Wang,J.;Zhang,J.Y.;Wang,R.;Li,P.;Wang,Y.T.Arctigenin suppresses renal interstitial fibrosis in a rat model of obstructive nephropathy.Phytomedicine 2017,30,28-41.
(12)Wang.J.L.;Cheng,L.P.;Wang,T.C.;Deng,W.;Wu,F.H.Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR,molecular docking,and dynamics simulation techniques.J.Mol.Graph.Model.2017,72,178-186.
(13)Shu,M.;Zhang,Y.R.;Tian,F.F.;Yang,L.;Lin,Z.H.Molecular docking and 3D-QSAR research of biphenyl carboxylic acid MMP-3 inhibitors.Chin.J.Struc.Chem.2012,31,443-451.
(14)Zhang,H.X.;Li,Y.;Wang,X.;Xiao,Z.T.;Wang,Y.H.Insight into the structural requirements of benzothiadiazine scaffold-based derivatives as hepatitis C virus NS5B polymerase inhibitors using 3D-QSAR,molecular docking and molecular dynamics.Curr.Med.Chem.2011,18,4019-4028.
(15)Yu,R.;Wang,J.;Wang,R.;Lin,Y.;Hu,Y.;Wang,Y.Q.;Shu,M.;Lin,Z.H.Combined pharmacophore modeling,3D-QSAR,homology modeling and docking studies on CYP11B1 inhibitors.Molecules 2015,20,1014-1030.