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A combination of 3D-QSAR, molecular docking and molecular dynamics simulation studies of benzimidazole-quinolinone derivatives as iNOS inhibitors.

Zhang H, Zan J, Yu G, Jiang M, Liu P - Int J Mol Sci (2012)

Bottom Line: A QSAR model with R(2) of 0.9356, Q(2) of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation.Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1) compounds with the proper-size hydrophobic substituents at position 3 in ring-C (R(3) substituent), hydrophilic substituents near the X(6) of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2) Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370.The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Tianjin Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin 300192, China; E-Mails: zhanghao27@126.com (H.Z.); sinokang123@yahoo.com.cn (J.Z.); yuguangyun123.good@163.com (G.Y.); jiangming_159@yahoo.com.cn (M.J.).

ABSTRACT
Inducible Nitric Oxide Synthase (iNOS) has been involved in a variety of diseases, and thus it is interesting to discover and optimize new iNOS inhibitors. In previous studies, a series of benzimidazole-quinolinone derivatives with high inhibitory activity against human iNOS were discovered. In this work, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking and molecular dynamics (MD) simulation approaches were applied to investigate the functionalities of active molecular interaction between these active ligands and iNOS. A QSAR model with R(2) of 0.9356, Q(2) of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation. Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1) compounds with the proper-size hydrophobic substituents at position 3 in ring-C (R(3) substituent), hydrophilic substituents near the X(6) of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2) Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370. The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors.

Show MeSH
Pictorial representation of the contours generated using the quantitative structure-activity relationships (QSAR) model. Hydrogen bond acceptor property and electron withdrawing features that arise when the QSAR model is applied to compounds 15 (a) and (c). Positive ionic and hydrophobic interactions features that arise when the QSAR model is applied to compounds 15 (b) and (d). Blue cubes favorable regions for activity, red cubes unfavorable region for activity.
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f2-ijms-13-11210: Pictorial representation of the contours generated using the quantitative structure-activity relationships (QSAR) model. Hydrogen bond acceptor property and electron withdrawing features that arise when the QSAR model is applied to compounds 15 (a) and (c). Positive ionic and hydrophobic interactions features that arise when the QSAR model is applied to compounds 15 (b) and (d). Blue cubes favorable regions for activity, red cubes unfavorable region for activity.

Mentions: The 3D-QSAR visualization can be generated by Phase, in which the blue cubes are favorable for activity and the red cubes are unfavorable. It could be concluded from Figure 2 that the heterocyclic ring-D may improve a compound’s activity because of the blue and red cubes observed at the ring-D. The corresponding compounds with heterocyclic ring-D (compounds 26, 34, 37, 38) are more active than compounds with aromatic ring-D (compounds 15, 18). Furthermore, presence of hydrophilic grouping around the 4-position of ring-D would enhance the iNOS inhibition according to Figure 2d. The structures of ligands 26 and 32 are identical except for the 7 position, while the activity of ligand 32 is interesting due to N in the 7 position. The red cubes at position 7 in ring-D indicated a positive potential of electron withdrawing, characteristic of the ligands from Figure 2c. For example, the activities of compounds 27, 28, 29, 30 were lower than compounds 31. The R3 in ring-C substituents of the 39 ligands was found not to be electron-withdrawing and quite sensitive to steric bulk from Figure 2c,d, such as an ethyl group (compound 11; pEC50 = 2.37) or expansion to a tertiary butyl group (compound 12; pEC50 = 1.32) which led to significant decreases in potency. However, the simple n-propyl substituent maintained activity (compound 13; pEC50 = 3.14). Cyclization of the isopropyl group to afford the cyclo-propyl derivative, compound 14, led to a minor loss in potency (compound 14; pEC50 = 2.80). However, upon expansion of the ring size to cyclo-butyl (compound 15; pEC50 = 3.59) or cyclo-pentyl (compound 16; pEC50 = 3.13), potency improved. Further increase in ring size like cyclo-hexyl of compound 17 led to a loss in potency (compound 17; pEC50 = 2.05), and thus demonstrated subtle R3 size requirements for optimal potency.


A combination of 3D-QSAR, molecular docking and molecular dynamics simulation studies of benzimidazole-quinolinone derivatives as iNOS inhibitors.

Zhang H, Zan J, Yu G, Jiang M, Liu P - Int J Mol Sci (2012)

Pictorial representation of the contours generated using the quantitative structure-activity relationships (QSAR) model. Hydrogen bond acceptor property and electron withdrawing features that arise when the QSAR model is applied to compounds 15 (a) and (c). Positive ionic and hydrophobic interactions features that arise when the QSAR model is applied to compounds 15 (b) and (d). Blue cubes favorable regions for activity, red cubes unfavorable region for activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472740&req=5

f2-ijms-13-11210: Pictorial representation of the contours generated using the quantitative structure-activity relationships (QSAR) model. Hydrogen bond acceptor property and electron withdrawing features that arise when the QSAR model is applied to compounds 15 (a) and (c). Positive ionic and hydrophobic interactions features that arise when the QSAR model is applied to compounds 15 (b) and (d). Blue cubes favorable regions for activity, red cubes unfavorable region for activity.
Mentions: The 3D-QSAR visualization can be generated by Phase, in which the blue cubes are favorable for activity and the red cubes are unfavorable. It could be concluded from Figure 2 that the heterocyclic ring-D may improve a compound’s activity because of the blue and red cubes observed at the ring-D. The corresponding compounds with heterocyclic ring-D (compounds 26, 34, 37, 38) are more active than compounds with aromatic ring-D (compounds 15, 18). Furthermore, presence of hydrophilic grouping around the 4-position of ring-D would enhance the iNOS inhibition according to Figure 2d. The structures of ligands 26 and 32 are identical except for the 7 position, while the activity of ligand 32 is interesting due to N in the 7 position. The red cubes at position 7 in ring-D indicated a positive potential of electron withdrawing, characteristic of the ligands from Figure 2c. For example, the activities of compounds 27, 28, 29, 30 were lower than compounds 31. The R3 in ring-C substituents of the 39 ligands was found not to be electron-withdrawing and quite sensitive to steric bulk from Figure 2c,d, such as an ethyl group (compound 11; pEC50 = 2.37) or expansion to a tertiary butyl group (compound 12; pEC50 = 1.32) which led to significant decreases in potency. However, the simple n-propyl substituent maintained activity (compound 13; pEC50 = 3.14). Cyclization of the isopropyl group to afford the cyclo-propyl derivative, compound 14, led to a minor loss in potency (compound 14; pEC50 = 2.80). However, upon expansion of the ring size to cyclo-butyl (compound 15; pEC50 = 3.59) or cyclo-pentyl (compound 16; pEC50 = 3.13), potency improved. Further increase in ring size like cyclo-hexyl of compound 17 led to a loss in potency (compound 17; pEC50 = 2.05), and thus demonstrated subtle R3 size requirements for optimal potency.

Bottom Line: A QSAR model with R(2) of 0.9356, Q(2) of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation.Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1) compounds with the proper-size hydrophobic substituents at position 3 in ring-C (R(3) substituent), hydrophilic substituents near the X(6) of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2) Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370.The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Tianjin Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin 300192, China; E-Mails: zhanghao27@126.com (H.Z.); sinokang123@yahoo.com.cn (J.Z.); yuguangyun123.good@163.com (G.Y.); jiangming_159@yahoo.com.cn (M.J.).

ABSTRACT
Inducible Nitric Oxide Synthase (iNOS) has been involved in a variety of diseases, and thus it is interesting to discover and optimize new iNOS inhibitors. In previous studies, a series of benzimidazole-quinolinone derivatives with high inhibitory activity against human iNOS were discovered. In this work, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking and molecular dynamics (MD) simulation approaches were applied to investigate the functionalities of active molecular interaction between these active ligands and iNOS. A QSAR model with R(2) of 0.9356, Q(2) of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation. Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1) compounds with the proper-size hydrophobic substituents at position 3 in ring-C (R(3) substituent), hydrophilic substituents near the X(6) of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2) Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370. The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors.

Show MeSH