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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 conformation of compound 34 after MD simulation (red) and compound 34’s pose of the ADHHR.89 model (green).
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f5-ijms-13-11210: Superposition of conformation of compound 34 after MD simulation (red) and compound 34’s pose of the ADHHR.89 model (green).

Mentions: Compared with molecular docking results, MD simulation results of compound 34 showed a similar binding mode, lending credit to the reliability of active conformations obtained by Glide. Besides, the mode of the most potent inhibitors, 34 resembles the 34’s pose of the ADHHR.89 model as shown in Figure 5. David et al. proposed that there is a direct correlation between inhibitory capability of a compound and the folding of a helix [15]. Their study revealed that inhibitors occupied the Glu371 which is part of the helix, thus displacing helix side chains from the Arg binding site and disrupting part of the dimer interface, finally blocking the formation of the protein-protein interaction present in the dimeric form of iNOS [8,10]. In view of these facts, the analysis of root-mean-square fluctuation (RMSF) versus the residue number for system-I and system-II is illustrated in panel a of Figure 6. It can be seen that there are four major flexible protein segments corresponding to residues 264–272, 327–337, 370–380, 389–409 in system-II. The fluctuations of these residues are higher in the 34-bound system than those in the 12-bound system. The active site, including Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485, also have larger conformational drift for the 34-bound system than those for the 12-bound system. Compared with system-II, the protein structure of system-I changed equably and the fluctuations of the residues are small. Besides, the RMSF of residues in the active site also seemed relatively wavy, which could be caused by movement of the heme during MD simulation in view of its particular structure and function in iNOS.


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 conformation of compound 34 after MD simulation (red) and compound 34’s pose of the ADHHR.89 model (green).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5-ijms-13-11210: Superposition of conformation of compound 34 after MD simulation (red) and compound 34’s pose of the ADHHR.89 model (green).
Mentions: Compared with molecular docking results, MD simulation results of compound 34 showed a similar binding mode, lending credit to the reliability of active conformations obtained by Glide. Besides, the mode of the most potent inhibitors, 34 resembles the 34’s pose of the ADHHR.89 model as shown in Figure 5. David et al. proposed that there is a direct correlation between inhibitory capability of a compound and the folding of a helix [15]. Their study revealed that inhibitors occupied the Glu371 which is part of the helix, thus displacing helix side chains from the Arg binding site and disrupting part of the dimer interface, finally blocking the formation of the protein-protein interaction present in the dimeric form of iNOS [8,10]. In view of these facts, the analysis of root-mean-square fluctuation (RMSF) versus the residue number for system-I and system-II is illustrated in panel a of Figure 6. It can be seen that there are four major flexible protein segments corresponding to residues 264–272, 327–337, 370–380, 389–409 in system-II. The fluctuations of these residues are higher in the 34-bound system than those in the 12-bound system. The active site, including Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485, also have larger conformational drift for the 34-bound system than those for the 12-bound system. Compared with system-II, the protein structure of system-I changed equably and the fluctuations of the residues are small. Besides, the RMSF of residues in the active site also seemed relatively wavy, which could be caused by movement of the heme during MD simulation in view of its particular structure and function in iNOS.

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