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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
The results of molecular dynamics (MD) simulation. The MD simulation time vs. root mean-square deviation (RMSD, in Å) of the backbone atoms for the system-I (green), the 34-bound system (black) and the 12-bound system (red).
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f4-ijms-13-11210: The results of molecular dynamics (MD) simulation. The MD simulation time vs. root mean-square deviation (RMSD, in Å) of the backbone atoms for the system-I (green), the 34-bound system (black) and the 12-bound system (red).

Mentions: In the docking studies, flexibility of the protein was not taken into consideration. In order to confirm binding modes of ligands and to give the whole impression of the benzimidazole-quinolinone derivatives, we performed MD simulations with the Desmond program. On the whole, the coordinates of active site residues of inhibitors bound to iNOS may be different to the coordinates of free iNOS. For this reason, two different systems were used in our MD simulations: The first one was the iNOS and solvent (water) molecules (system-I), and the second was a rectangular box which included benzimidazole-quinolinone analogues in the binding site of the enzyme (system-II). System-I was run as a control, and compound 34 as the most potent compound, and compound 12 with low activity in Table 1 were docked in the binding site of iNOS. The 12-bound system and the 34-bound system consisted of system-II. To explore the dynamic stability of systems and ensure the rationality of the sampling method, RMSD from the starting structure was analyzed as depicted in Figure 4. After 10 ns, the RMSD of system-I and system-II was about 4.5 Å and 3 Å respectively, and both of them almost remained at their own levels in the following simulation process. This indicated that the complex structure is stable after 10 ns of simulation. Average conformations of system-I and II were derived from the last 160 conformations in the last 2 ns MD simulations.


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)

The results of molecular dynamics (MD) simulation. The MD simulation time vs. root mean-square deviation (RMSD, in Å) of the backbone atoms for the system-I (green), the 34-bound system (black) and the 12-bound system (red).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4-ijms-13-11210: The results of molecular dynamics (MD) simulation. The MD simulation time vs. root mean-square deviation (RMSD, in Å) of the backbone atoms for the system-I (green), the 34-bound system (black) and the 12-bound system (red).
Mentions: In the docking studies, flexibility of the protein was not taken into consideration. In order to confirm binding modes of ligands and to give the whole impression of the benzimidazole-quinolinone derivatives, we performed MD simulations with the Desmond program. On the whole, the coordinates of active site residues of inhibitors bound to iNOS may be different to the coordinates of free iNOS. For this reason, two different systems were used in our MD simulations: The first one was the iNOS and solvent (water) molecules (system-I), and the second was a rectangular box which included benzimidazole-quinolinone analogues in the binding site of the enzyme (system-II). System-I was run as a control, and compound 34 as the most potent compound, and compound 12 with low activity in Table 1 were docked in the binding site of iNOS. The 12-bound system and the 34-bound system consisted of system-II. To explore the dynamic stability of systems and ensure the rationality of the sampling method, RMSD from the starting structure was analyzed as depicted in Figure 4. After 10 ns, the RMSD of system-I and system-II was about 4.5 Å and 3 Å respectively, and both of them almost remained at their own levels in the following simulation process. This indicated that the complex structure is stable after 10 ns of simulation. Average conformations of system-I and II were derived from the last 160 conformations in the last 2 ns MD simulations.

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