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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.

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(a) Docked structures of all 39 inhibitors; (b) The binding site formed around compound 34; (c) The binding site formed around compound 12.
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f3-ijms-13-11210: (a) Docked structures of all 39 inhibitors; (b) The binding site formed around compound 34; (c) The binding site formed around compound 12.

Mentions: Figure 3a showed that all 39 inhibitors were docked into the binding pocket of iNOS. All molecules were positioned in the same way, and most of them shared a similar binding mode except for several molecules deviating from the atom Fe due to low activity with unfavorable features for the binding process. The binding modes of the most active compound, compound 34, and compound 12 with the least activity are shown in panels b and c of Figure 3, respectively.


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)

(a) Docked structures of all 39 inhibitors; (b) The binding site formed around compound 34; (c) The binding site formed around compound 12.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ijms-13-11210: (a) Docked structures of all 39 inhibitors; (b) The binding site formed around compound 34; (c) The binding site formed around compound 12.
Mentions: Figure 3a showed that all 39 inhibitors were docked into the binding pocket of iNOS. All molecules were positioned in the same way, and most of them shared a similar binding mode except for several molecules deviating from the atom Fe due to low activity with unfavorable features for the binding process. The binding modes of the most active compound, compound 34, and compound 12 with the least activity are shown in panels b and c of Figure 3, respectively.

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