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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
Superposition of co-crystallized BBS-4 (gray) and Glide dock (green).
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f8-ijms-13-11210: Superposition of co-crystallized BBS-4 (gray) and Glide dock (green).

Mentions: Molecular docking was performed to further investigate the binding mode between crucial functional groups of benzimidazole-quinolinone derivatives and iNOS. It also aided in understanding the structure-activity relationship revealed by QSAR. Glide was applied to perform the docking studies. Glide approximated a complete systematic search of the conformational, orientational and positional space of the docked ligand, and a series of hierarchical filters was used to search for possible locations of the ligand in the active-site region [30,32]. In this work, grid box was centered on the ligand BBS-4 centroid in the X-ray crystal structure of iNOS (PDB code: 2ORO) and the docking ligand was treated flexibly while the protein was held rigidly in the docking procedure. The RMSD value for heavy atoms of the ligand BBS-4 between the Glide-generated docked pose and the native pose was 0.79 Å (Figure 8). The low RMSD value between the docked pose and the input geometry indicated that the Glide program was able to reproduce the native conformation successfully.


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)

Superposition of co-crystallized BBS-4 (gray) and Glide dock (green).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8-ijms-13-11210: Superposition of co-crystallized BBS-4 (gray) and Glide dock (green).
Mentions: Molecular docking was performed to further investigate the binding mode between crucial functional groups of benzimidazole-quinolinone derivatives and iNOS. It also aided in understanding the structure-activity relationship revealed by QSAR. Glide was applied to perform the docking studies. Glide approximated a complete systematic search of the conformational, orientational and positional space of the docked ligand, and a series of hierarchical filters was used to search for possible locations of the ligand in the active-site region [30,32]. In this work, grid box was centered on the ligand BBS-4 centroid in the X-ray crystal structure of iNOS (PDB code: 2ORO) and the docking ligand was treated flexibly while the protein was held rigidly in the docking procedure. The RMSD value for heavy atoms of the ligand BBS-4 between the Glide-generated docked pose and the native pose was 0.79 Å (Figure 8). The low RMSD value between the docked pose and the input geometry indicated that the Glide program was able to reproduce the native conformation successfully.

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