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Design and prediction of new anticoagulants as a selective Factor IXa inhibitor via three-dimensional quantitative structure-property relationships of amidinobenzothiophene derivatives.

Gao JS, Tong XP, Chang YQ, He YX, Mei YD, Tan PH, Guo JL, Liao GC, Xiao GK, Chen WM, Zhou SF, Sun PH - Drug Des Devel Ther (2015)

Bottom Line: Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants.Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping.On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.

ABSTRACT
Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants. Eighty-four amidinobenzothiophene antithrombotic derivatives targeting FIXa were selected to establish three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis and comparative similarity indices analysis methods. Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping. The satisfactory q (2) values of 0.753 and 0.770, and r (2) values of 0.940 and 0.965 for 3D-QSAR and 3D-QSSR, respectively, indicated that the models are available to predict both the inhibitory activity and selectivity on FIXa against Factor Xa, the activated status of Factor X. This work revealed that the steric, hydrophobic, and H-bond factors should appropriately be taken into account in future rational design, especially the modifications at the 2'-position of the benzene and the 6-position of the benzothiophene in the R group, providing helpful clues to design more active and selective FIXa inhibitors for the treatment of thrombosis. On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.

No MeSH data available.


Related in: MedlinePlus

A 2-amidinobenzothiophene ring with structural rigidity, comprising the common core of all molecules in the data set, was selected as the common substructure to align all of the molecules (A) Template used for molecular alignment of benzothiophene derivatives (Compound 33). (B) Molecular alignment.
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f1-dddt-9-1743: A 2-amidinobenzothiophene ring with structural rigidity, comprising the common core of all molecules in the data set, was selected as the common substructure to align all of the molecules (A) Template used for molecular alignment of benzothiophene derivatives (Compound 33). (B) Molecular alignment.

Mentions: Molecular alignment is considered to be one of the most essential elements that extensively influence the quality and the predictive ability of the models in CoMFA and CoMSIA analyses, although other factors such as lattice shifting step size, probe atom type, and orientation of the aligned compounds might have influence on the results as well.23,24 A 2-amidinobenzothiophene ring with structural rigidity, comprising the common core of all molecules in the data set, was selected as the common substructure to align all of the molecules (Figure 1). Active conformation selection is a key step for 3D-QSAR analysis, and in the present study, the molecular conformation of Compound 33 (the most active compound) obtained from the molecular docking was used as the template to build molecular structures of all the compounds. It can be seen from Figure 1 that all the compounds studied have similar bioactive conformations.


Design and prediction of new anticoagulants as a selective Factor IXa inhibitor via three-dimensional quantitative structure-property relationships of amidinobenzothiophene derivatives.

Gao JS, Tong XP, Chang YQ, He YX, Mei YD, Tan PH, Guo JL, Liao GC, Xiao GK, Chen WM, Zhou SF, Sun PH - Drug Des Devel Ther (2015)

A 2-amidinobenzothiophene ring with structural rigidity, comprising the common core of all molecules in the data set, was selected as the common substructure to align all of the molecules (A) Template used for molecular alignment of benzothiophene derivatives (Compound 33). (B) Molecular alignment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376188&req=5

f1-dddt-9-1743: A 2-amidinobenzothiophene ring with structural rigidity, comprising the common core of all molecules in the data set, was selected as the common substructure to align all of the molecules (A) Template used for molecular alignment of benzothiophene derivatives (Compound 33). (B) Molecular alignment.
Mentions: Molecular alignment is considered to be one of the most essential elements that extensively influence the quality and the predictive ability of the models in CoMFA and CoMSIA analyses, although other factors such as lattice shifting step size, probe atom type, and orientation of the aligned compounds might have influence on the results as well.23,24 A 2-amidinobenzothiophene ring with structural rigidity, comprising the common core of all molecules in the data set, was selected as the common substructure to align all of the molecules (Figure 1). Active conformation selection is a key step for 3D-QSAR analysis, and in the present study, the molecular conformation of Compound 33 (the most active compound) obtained from the molecular docking was used as the template to build molecular structures of all the compounds. It can be seen from Figure 1 that all the compounds studied have similar bioactive conformations.

Bottom Line: Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants.Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping.On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People's Republic of China.

ABSTRACT
Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants. Eighty-four amidinobenzothiophene antithrombotic derivatives targeting FIXa were selected to establish three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis and comparative similarity indices analysis methods. Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping. The satisfactory q (2) values of 0.753 and 0.770, and r (2) values of 0.940 and 0.965 for 3D-QSAR and 3D-QSSR, respectively, indicated that the models are available to predict both the inhibitory activity and selectivity on FIXa against Factor Xa, the activated status of Factor X. This work revealed that the steric, hydrophobic, and H-bond factors should appropriately be taken into account in future rational design, especially the modifications at the 2'-position of the benzene and the 6-position of the benzothiophene in the R group, providing helpful clues to design more active and selective FIXa inhibitors for the treatment of thrombosis. On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.

No MeSH data available.


Related in: MedlinePlus