Limits...
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

Chemical structures.(A) C_773 (B) C_997.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4524694&req=5

pone.0134691.g004: Chemical structures.(A) C_773 (B) C_997.

Mentions: A set of 35 top scoring molecules, generated using growing and linking strategy were then used for molecular docking. All the molecules were first prepared using LigPrep. These molecules were then docked against the active site of COX-2 protein using the XP docking protocol of Glide. The compounds with docking score more than 8.00 (S1 Table) were then docked against the active site of COX-1 protein. Two compounds with least score for COX-1, named as C_773 and C_997 were then chosen for further consideration (S1 Table). IUPAC name of C_773 and C_997 is 5,5-dihydrogenio-3-[(1Z)-1-[4-({3-hydroxy-4-[hydroxy(λ3-oxidanidylidene)methyl]phenyl}carbamoyl)phenyl]prop-1-en-1-yl]-1H-1,2,4-triazol-2-ium and (3R)-3-carbamoyl-5-[(1Z)-1-{4-[(4-carboxy-3-hydroxyphenyl)carbamoyl]phenyl}prop-1-en-1-yl]-3H-1,2,4-triazol-1-ium respectively and their chemical structures is shown in Fig 4. These molecules had high binding affinity for the COX-2 binding pocket and less affinity for the active site of COX-1 enzyme. Hence, these compounds can be suggested as selective towards COX-2. C_773 had a docking score of -10.298 kcal/mol with COX-2 and -3.806 kcal/mol with COX-1. Similarly C_997 had a glide docking score of -8.688 kcal/mol with COX-2 and -3.435 kcal/mol with COX-1.


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)

Chemical structures.(A) C_773 (B) C_997.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134691.g004: Chemical structures.(A) C_773 (B) C_997.
Mentions: A set of 35 top scoring molecules, generated using growing and linking strategy were then used for molecular docking. All the molecules were first prepared using LigPrep. These molecules were then docked against the active site of COX-2 protein using the XP docking protocol of Glide. The compounds with docking score more than 8.00 (S1 Table) were then docked against the active site of COX-1 protein. Two compounds with least score for COX-1, named as C_773 and C_997 were then chosen for further consideration (S1 Table). IUPAC name of C_773 and C_997 is 5,5-dihydrogenio-3-[(1Z)-1-[4-({3-hydroxy-4-[hydroxy(λ3-oxidanidylidene)methyl]phenyl}carbamoyl)phenyl]prop-1-en-1-yl]-1H-1,2,4-triazol-2-ium and (3R)-3-carbamoyl-5-[(1Z)-1-{4-[(4-carboxy-3-hydroxyphenyl)carbamoyl]phenyl}prop-1-en-1-yl]-3H-1,2,4-triazol-1-ium respectively and their chemical structures is shown in Fig 4. These molecules had high binding affinity for the COX-2 binding pocket and less affinity for the active site of COX-1 enzyme. Hence, these compounds can be suggested as selective towards COX-2. C_773 had a docking score of -10.298 kcal/mol with COX-2 and -3.806 kcal/mol with COX-1. Similarly C_997 had a glide docking score of -8.688 kcal/mol with COX-2 and -3.435 kcal/mol with COX-1.

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