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Computational Structure-Based De Novo Design of Hypothetical Inhibitors against the Anti- Inflammatory Target COX-2.

Dhanjal JK, Sreenidhi AK, Bafna K, Katiyar SP, Goyal S, Grover A, Sundar D - PLoS ONE (2015)

Bottom Line: Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity.The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules.The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemical Engineering and Biotechnology, Indian institute of Technology Delhi, New Delhi, India.

ABSTRACT
Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti-inflammatory drugs since long. Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach. A library of 2657 drug like molecules was generated. 2D fingerprinting based screening of the designed library gave a unique set of compounds. Molecular docking approach was then used to identify two compounds highly specific for COX-2 isoform. Molecular dynamics simulations of protein-ligand complexes revealed that the candidate ligands were dynamically stable within the cyclooxygenase binding site of COX-2. The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules. The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use.

No MeSH data available.


Related in: MedlinePlus

Molecular dynamics simulation of COX-2-C_997 complex.(A) RMSD trajectory of the protein backbone in reference to the structure obtained subsequent to docking. (B) Superimposition of the complex before and after simulation run. (C) Molecular interactions between the two partners. Hydrogen bond forming residues are shown in green and hydrophobically interacting residues are shown in blue.
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pone.0134691.g007: Molecular dynamics simulation of COX-2-C_997 complex.(A) RMSD trajectory of the protein backbone in reference to the structure obtained subsequent to docking. (B) Superimposition of the complex before and after simulation run. (C) Molecular interactions between the two partners. Hydrogen bond forming residues are shown in green and hydrophobically interacting residues are shown in blue.

Mentions: The protein receptor is considered rigid in nature during semi-flexible docking methods. To get a more realistic picture of the interactions between protein and the ligands, the docked complexes were simulated in a water box for about 50 ns. For both the complexes, RMSD of the protein backbone in reference to the structure obtained subsequent to docking was plotted against time for the entire simulation run (Figs 6 (A) and 7 (A)). Frames were extracted from the stable trajectory between 40 to 50 ns for C_773 and 35 to 50 ns for C_997 to compute the average structure.


Computational Structure-Based De Novo Design of Hypothetical Inhibitors against the Anti- Inflammatory Target COX-2.

Dhanjal JK, Sreenidhi AK, Bafna K, Katiyar SP, Goyal S, Grover A, Sundar D - PLoS ONE (2015)

Molecular dynamics simulation of COX-2-C_997 complex.(A) RMSD trajectory of the protein backbone in reference to the structure obtained subsequent to docking. (B) Superimposition of the complex before and after simulation run. (C) Molecular interactions between the two partners. Hydrogen bond forming residues are shown in green and hydrophobically interacting residues are shown in blue.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524694&req=5

pone.0134691.g007: Molecular dynamics simulation of COX-2-C_997 complex.(A) RMSD trajectory of the protein backbone in reference to the structure obtained subsequent to docking. (B) Superimposition of the complex before and after simulation run. (C) Molecular interactions between the two partners. Hydrogen bond forming residues are shown in green and hydrophobically interacting residues are shown in blue.
Mentions: The protein receptor is considered rigid in nature during semi-flexible docking methods. To get a more realistic picture of the interactions between protein and the ligands, the docked complexes were simulated in a water box for about 50 ns. For both the complexes, RMSD of the protein backbone in reference to the structure obtained subsequent to docking was plotted against time for the entire simulation run (Figs 6 (A) and 7 (A)). Frames were extracted from the stable trajectory between 40 to 50 ns for C_773 and 35 to 50 ns for C_997 to compute the average structure.

Bottom Line: Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity.The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules.The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemical Engineering and Biotechnology, Indian institute of Technology Delhi, New Delhi, India.

ABSTRACT
Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti-inflammatory drugs since long. Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach. A library of 2657 drug like molecules was generated. 2D fingerprinting based screening of the designed library gave a unique set of compounds. Molecular docking approach was then used to identify two compounds highly specific for COX-2 isoform. Molecular dynamics simulations of protein-ligand complexes revealed that the candidate ligands were dynamically stable within the cyclooxygenase binding site of COX-2. The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules. The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use.

No MeSH data available.


Related in: MedlinePlus