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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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Average conformation of the binding pocket of iNOS (2ORO) and compounds, derived from the last 160 conformations in the last 2 ns MD simulation. Coordination bonds and hydrogen bonds are shown in dashed lines (yellow). (a) Compound 34; (b) Compound 12.
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f7-ijms-13-11210: Average conformation of the binding pocket of iNOS (2ORO) and compounds, derived from the last 160 conformations in the last 2 ns MD simulation. Coordination bonds and hydrogen bonds are shown in dashed lines (yellow). (a) Compound 34; (b) Compound 12.

Mentions: Average conformations of the binding pocket of iNOS in system-II during the last 2 ns of simulation are depicted in Figure 7. For the 34-bound system, compound 34 occupies the binding pocket. The quinolinone coordinates to the Fe atom, setting the inhibitors into the protein. The substituent of the benzimidazole points back towards the porphyrin, and fills the pocket. The benzimidazole as the linker between the substituent and quinolinone is critical because sufficient flexibility and distance between the two groups are needed to accommodate the bend of the two aromatics and the binding ability of the compounds to the enzyme. Furthermore, the steric amino acid residues around compound 34 at the binding site are shown in Figure 7a. Clearly, no steric amino acid residues appear around positions X7 in ring-D (substituent Y), therefore, the substituents at positions X7 (conpounds 28, 29, 30, 31) in ring-D improve the activity. However, several crucial amino acid residues are found near some specific positions in the molecules. For example, Trp366, Met368, Tyr367 lies near position 2 (ring-A). It is clear that the aromatic residue Tyr367 can participate in a π–π stacking interaction with ring-A in molecule 34. At the same time, an H-bond with Met368 is formed. Thus, we can conclude that ring-A plays an important role in this binding pocket, due to its ability to form hydrogen-bonds and π-stacking interactions with some residues. Besides, hydrophobic amino acid residues Phe363 and Val346 appear near the X6 of ring-D, indicating that molecules with hydrophilic or polar groups (compound 24; pEC50 = 1.745) in this area may possess lower binding affinities to iNOS. Moreover, in the same region, the hydrophilic substituent was preferred according to pictorial representation of the contours generated using the QSAR model from Figure 2d. Oversize groups at position 2 of ring-C (compound 5, 6, 7, 8, 9) may be faced with resistance from the hydrophilic residue Tyr485, thereby impairing the activity. On the contrary, compound 12 exhibits lower stability during the 12 ns of the simulation because there is no strong interaction with the Fe atom of the heme. As ring-A and ring-B with hydrophobic groups tend to be away from the heme, the conformation of the protein is altered and the space around the heme becomes more confined. The hydrogen bond acceptor favored region in ring-B is located in the verge of the active site, and the remarkable interactions of this group with some important residues could not be found in the MD results. The ring-C and substituent R3 are located at similar positions compared to the MD result of the 34-bound system, but it was observed that most residues in this area such as Asn364, Gly365, Gln257 are not favored with the hydrophobic substituent R3 from panel b of Figure 7. This is an appropriate reason to explain why compound 12 exhibits weak inhibitory activity. These results further confirmed our results from the 3D-QSAR model, and revealed that the binding stabilization is consistant with the experimental activities.


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)

Average conformation of the binding pocket of iNOS (2ORO) and compounds, derived from the last 160 conformations in the last 2 ns MD simulation. Coordination bonds and hydrogen bonds are shown in dashed lines (yellow). (a) Compound 34; (b) Compound 12.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7-ijms-13-11210: Average conformation of the binding pocket of iNOS (2ORO) and compounds, derived from the last 160 conformations in the last 2 ns MD simulation. Coordination bonds and hydrogen bonds are shown in dashed lines (yellow). (a) Compound 34; (b) Compound 12.
Mentions: Average conformations of the binding pocket of iNOS in system-II during the last 2 ns of simulation are depicted in Figure 7. For the 34-bound system, compound 34 occupies the binding pocket. The quinolinone coordinates to the Fe atom, setting the inhibitors into the protein. The substituent of the benzimidazole points back towards the porphyrin, and fills the pocket. The benzimidazole as the linker between the substituent and quinolinone is critical because sufficient flexibility and distance between the two groups are needed to accommodate the bend of the two aromatics and the binding ability of the compounds to the enzyme. Furthermore, the steric amino acid residues around compound 34 at the binding site are shown in Figure 7a. Clearly, no steric amino acid residues appear around positions X7 in ring-D (substituent Y), therefore, the substituents at positions X7 (conpounds 28, 29, 30, 31) in ring-D improve the activity. However, several crucial amino acid residues are found near some specific positions in the molecules. For example, Trp366, Met368, Tyr367 lies near position 2 (ring-A). It is clear that the aromatic residue Tyr367 can participate in a π–π stacking interaction with ring-A in molecule 34. At the same time, an H-bond with Met368 is formed. Thus, we can conclude that ring-A plays an important role in this binding pocket, due to its ability to form hydrogen-bonds and π-stacking interactions with some residues. Besides, hydrophobic amino acid residues Phe363 and Val346 appear near the X6 of ring-D, indicating that molecules with hydrophilic or polar groups (compound 24; pEC50 = 1.745) in this area may possess lower binding affinities to iNOS. Moreover, in the same region, the hydrophilic substituent was preferred according to pictorial representation of the contours generated using the QSAR model from Figure 2d. Oversize groups at position 2 of ring-C (compound 5, 6, 7, 8, 9) may be faced with resistance from the hydrophilic residue Tyr485, thereby impairing the activity. On the contrary, compound 12 exhibits lower stability during the 12 ns of the simulation because there is no strong interaction with the Fe atom of the heme. As ring-A and ring-B with hydrophobic groups tend to be away from the heme, the conformation of the protein is altered and the space around the heme becomes more confined. The hydrogen bond acceptor favored region in ring-B is located in the verge of the active site, and the remarkable interactions of this group with some important residues could not be found in the MD results. The ring-C and substituent R3 are located at similar positions compared to the MD result of the 34-bound system, but it was observed that most residues in this area such as Asn364, Gly365, Gln257 are not favored with the hydrophobic substituent R3 from panel b of Figure 7. This is an appropriate reason to explain why compound 12 exhibits weak inhibitory activity. These results further confirmed our results from the 3D-QSAR model, and revealed that the binding stabilization is consistant with the experimental activities.

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