Virtual Analysis of Condensed Pyrimidine Derivatives as COX II Inhibitors Potential Anti-inflammatory Agents

 

S. A. Khedkar¹, J. S. Patil², P. M. Sabale³

¹Department of Pharmaceutical Chemistry, JNT University, Kakinada, Andhra Pradesh, India.

²Shivajirao Jondhale College of Pharmacy, Asangaon, Maharashtra, India.

³Rashtrasant Tukadoji Maharaj University, Nagpur, Maharashtra, India.

 

ABSTRACT:

Drug design and development is an interactive process includes process like molecular docking which involves virtual analysis of the derivatives against the protein targets. COXS are the groups of enzymes which plays vital role in the human process. COX II is important enzyme involved in the inflammation and can act as potential target for development of the potent anti-inflammatory agents. Pyrimidine is one of the most utilized heterocyclic scaffolds for the development of therapeutic agents due to its role in the nucleic acid and proteins in the human body. The present communication deals with docking analysis of virtually designed 58 condensed pyrimidine derivatives as potential anti-inflammatory agents. The derivatives were designed and virtually screened via molecular docking against the COX-II crystal structure to identically the potential leads.

 

 

INTRODUCTION:

Inflammation is the body response to the any cell injury or the infection mediated through the enzyme systems like COX 1 and COX 2. Inhibition of the COX enzymes is one of the important routes to develop potent anti-inflammatory agents. Computer aided drug design is an interactive technology for fast development of the drugs. Molecular docking is the process which involves study and analysis of the ligand protein interaction. Docking analysis was utililsed to screen large database of the molecule to find out ligands which gave ability to bind with protein targets, thus which can minimize the experimental work. Pyrimidine is two nitrogen containing heterocycle commonly observed in the protein and nucleic acids. Number of pyrimidine derivatives is reported for biological activity like antifungal, anticancer, antimicrobial, anti-inflammatory, antihistamic, antiamoebic, hypoglycemic activity and anthelmintic activity. In this present communication we report the virtual analysis of designed 58 condensed pyrimidine derivatives against crystal structure of COX –II for development of potent anti-inflammatory agents.

 

Experimental:

Selection of Protein:

Structure of celecoxib bound at the COX-2 active site (3LN1) utilized for docking analysis was downloaded from the free protein database www.rcsb.org.^36-37 Downloaded protein structure was then prepared using biopredicta module of the V life MDS 4.3.

 

Preparation of ligands:

The ligand structures as shown in table no 1 was developed using molecule builder module of the V life MDS 4.3. Ligands structures were drawn using 2D molecule builder and converted 3D structures and optimized via application of MMFF. These optimized ligand structures were further utilized for the docking analysis.

 

Table No 1: Table Showing Molecules under study

Molecule	Canonical SMILES
Molecule 1	c1ccc(cc1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 2	Clc1cccc(c1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 3	Fc1ccc(cc1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 4	Fc1ccc(cc1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 5	Clc1cccc(c1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 6	Cc1cccc(c1Nc1nc(nc2c1cccc2)c1ccccc1)C
Molecule 7	Clc1ccc(c(c1)N(=O)=O)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 8	Brc1ccc(cc1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 9	COc1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 10	COc1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 11	COc1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 12	Clc1cc(ccc1Nc1nc(nc2c1cccc2)c1ccccc1)N (=O)=O
Molecule 13	O=N(=O)c1cc(ccc1Nc1nc(nc2c1cccc2) c1ccccc1)N(=O)=O
Molecule 14	Cc1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 15	Cc1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 16	Cc1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 17	Clc1ccc(cc1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 18	O=N(=O)c1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 19	O=N(=O)c1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 20	O=N(=O)c1ccccc1Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 21	[CH]1NNC(N1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 22	c1ccc(cc1)c1nc(NC2N=CN[S+]2)c2c(n1) cccc2
Molecule 23	c1ccc(cc1)c1nnc(s1)Nc1nc(nc2c1cccc2)c1ccccc1
Molecule 24	Nc1ccc(cc1)c1nnc(s1)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 25	O=N(=O)c1ccc(cc1)c1nnc(s1)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 26	Oc1ccc(cc1)c1nnc(s1)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 27	CC(=O)c1ccccc1c1nnc(s1)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 28	c1ccc(cc1)/C=C/c1nnc(s1)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 29	Nc1ccccc1c1nnc(s1)Nc1nc(nc2c1cccc2) c1ccccc1
Molecule 30	c1ccc(cc1)Nc1ncnc2c1cccc2
Molecule 31	Clc1cccc(c1)Nc1ncnc2c1cccc2
Molecule 32	Fc1cccc(c1)Nc1ncnc2c1cccc2
Molecule 33	Fc1ccccc1Nc1ncnc2c1cccc2
Molecule 34	Clc1ccccc1Nc1ncnc2c1cccc2
Molecule 35	Cc1cccc(c1Nc1ncnc2c1cccc2)C
Molecule 36	Clc1ccc(c(c1)N(=O)=O)Nc1ncnc2c1cccc2
Molecule 37	Brc1ccc(cc1)Nc1ncnc2c1cccc2
Molecule 38	COc1ccccc1Nc1ncnc2c1cccc2
Molecule 39	COc1ccccc1Nc1ncnc2c1cccc2
Molecule 40	COc1ccccc1Nc1ncnc2c1cccc2
Molecule 41	Clc1cc(ccc1Nc1ncnc2c1cccc2)N(=O)=O
Molecule 42	O=N(=O)c1cc(ccc1Nc1ncnc2c1cccc2)N(=O)=O
Molecule 43	Oc1ccccc1Nc1ncnc2c1cccc2
Molecule 44	Oc1ccccc1Nc1ncnc2c1cccc2
Molecule 45	Oc1ccccc1Nc1ncnc2c1cccc2
Molecule 46	Clc1ccc(cc1)Nc1ncnc2c1cccc2
Molecule 47	O=N(=O)c1ccccc1Nc1ncnc2c1cccc2
Molecule 48	O=N(=O)c1ccccc1Nc1ncnc2c1cccc2
Molecule 49	O=N(=O)c1ccccc1Nc1ncnc2c1cccc2
Molecule 50	c1nnc([nH]1)Nc1ncnc2c1cccc2
Molecule 51	n1c[nH]c([s+]1)Nc1ncnc2c1cccc2
Molecule 52	c1ccc(cc1)c1nnc(s1)Nc1ncnc2c1cccc2
Molecule 53	Nc1ccc(cc1)c1nnc(s1)Nc1ncnc2c1cccc2
Molecule 54	O=N(=O)c1ccc(cc1)c1nnc(s1)Nc1ncnc2c1cccc2
Molecule 55	Oc1ccc(cc1)c1nnc(s1)Nc1ncnc2c1cccc2
Molecule 56	CC(=O)c1ccccc1c1nnc(s1)Nc1ncnc2c1cccc2
Molecule 57	c1ccc(cc1)/C=C\c1nnc(s1)Nc1ncnc2c1cccc2
Molecule 58	Nc1ccccc1c1nnc(s1)Nc1ncnc2c1cccc2

 

Docking Studies

To explore binding potential of the molecule under study the docking simulation was performed using biopredicta module of the Vlife MDS 4.3. Grip based docking simulation was performed on the interactions of the compounds; we carried out binding simulations using biopredicta module of Vlife MDS 4.3 suite. Structure of the celecoxib bound at the COX-2 active site (PDB ID: 3LN1) was downloaded from the free protein database www.rscb.org and utilized for the docking analysis. Grip based docking simulation was performed to analyses the binding potential of molecules under study.

 

RESULTS AND DISCUSSION:

Molecular docking is an interactive technique on using which chemical structures can be analyzed for their binding potential prior to the synthesis of the ligands. Molecular docking was utilized to screen the ligands structures under study. All the ligand structures are analyzed via grip docking method. Molecule no 11 was found to be having binding potential and was found to be interacting with COX II via formation of hydrogen bond interaction with SER516, aromatic interactions with TYR334, TYR371, TRP373, PHE504 and hydrophobic interactions with LEU338, ILE503, PHE504as shown in figure 1.

 

Figure No1: Figure Showing Docking Interactions of Molecule No11

 

Derivative 23 is also found active in docking analysis was found to show Hydrogen bond interaction with TYR371, SER516 via formation of hydrogen bond and with HIS75, PHE191, TYR334, TYR341, TYR371, TRP373 PHE504 via formation of aromatic interactionsas shown in figure 2.

 

Figure No 2: Figure Showing Docking Interactions of Molecule No 23

 

Molecule 24 interacted with formation of hydrogen bond interaction with TYR371 and aromatic interactions with PHE184, TYR334, TRP373, PHE504, while derivative 25 interacted with enzyme via formation of hydrogen bond interaction with SER339, GLY340, LEU517 and aromatic interaction with HIS75, TYR341, PHE504as shown in figure 3 and 4.

 

Figure No3: Figure Showing Docking Interactions of Molecule No 24

 

Figure No4: Figure Showing Docking Interactions of Molecule No 25

 

Molecule no 26 interacted with TYR371 via formation of hydrogen bond and also interacted with PHE184, TYR334, TRP373, PHE504 via formation of aromatic interactionas shown in figure 5.

 

Figure No5: Figure Showing Docking Interactions of Molecule No 26

 

Derivative 27 interacted via formation of hydrogen bond with SER339 and aromatic interaction with HIS75, TYR341, and PHE504 as shown in figure 6.

 

Figure No6: Figure Showing Docking Interactions of Molecule No 27

 

Derivative 43 was interacted with target via formation of hydrogen bond with SER516 and aromatic interaction with TYR334, TRP373 PHE504 as shown in figure 7.

 

Figure No7 : Figure Showing Docking Interactions of Molecule No 43

 

CONCLUSION:

All the selected derivatives was found to be showing ability to bind with the COX II and showing excellent binding interactions. Results indicated heterocyclic derivatives are having better binding affinity than the other molecules. Further biological analysis will lead to development of potent and selective inhibitors of COX -II

 

ACKNOWLEDGEMENT:

Authors are thankful to Vlife Sciences for providing facility for research work.

 

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Accepted on 19.11.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(10):5423-5426.