Protein structure activity relationship of imatinib

protein structure activity relationship of imatinib

After the effective use of Imatinib as a therapeutic agent for Chronic Myeloid Structure Activity Relationship (SAR), Pharmacophore, Drug design, Imatinib, BCR-ABL encloses a protein tyrosine kinase activity After the Structure Activity Relationship (SAR), effective use of Imatinib as a This abnormal BCR- marrow stem cells known as Philadelphia ABL protein in turn. Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl inducers, inhibitors and structure-activity relationships of human Cytochrome.

protein structure activity relationship of imatinib

The 3D structure of our protein is available in Protein Data Bank. The selected protein 3D structure is having 4 chains, hence only chain A was isolated from the structure and used for docking. Autodock is used for the Molecular docking studies of the ligands with the receptor protein.

Autodock uses binding free energy evaluation to find the best binding mode. Autodock energy values were calculated by the characterization of intermolecular energy consist of van der Walls energy, hydrogen bonding energy, desolvation energy, and electrostatic energyinternal energy of ligand, and torsional free energy.

The designed ligands were subjected to molecular docking studies and the docked complex is visualized using Python molecule viewer 15 as shown in Fig. Analogues have been designed by taking Imatinib as a prototype. Substitutions have been made by —OH, -NH2 and -Cl at position -R, -R1, -R2, -R3, —R4 and —R5 in such a way that binding energy, molecular properties Druglikeness score, Hydrogen bond donor, hydrogen bond acceptor etc and other pharmacological properties Absorption, Distribution, Metabolism, Excretion, Toxicity etc are higher than that of the prototype as discussed in Table 2, 3, 4, 5.

Pictures have been taken from server http: The metabolic sites of these designed drugs have been predicted using MetaPrint2D 18 as shown in Fig.

ADME and toxicity was predicted using admetexp server When methyl group of Imatinib at position —R was substituted with —OH, -NH2 and —Cl group then our results showed that substituted ligands are having better pharmacological property as compared to Imatinib. But the ligand which is substituted with hydroxyl group IA-1 is showing best result as compared with amine and chloride substituted ligands IA-2 and IA-3 as shown in the Table 1, 2, 3, 4 and 5.

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Thus further substitution was carried out at position -R1, -R2, -R3, —R4 and —R5 after keeping hydroxyl group substitution static at position —R. When the substitution of —OH, -NH2 and —Cl group was done at position -R1 after keeping hydroxyl group substitution static at position —Rthen our results showed that substituted ligands are having more better property as compared to hydroxyl group substituted ligand at position —R.

But the ligand which is substituted with hydroxyl group IA-4 is showing better result as compared to amine and chloride substituted ligands IA-5 and IA-6 as shown in the Table 1, 2, 3, 4 and 5. Thus further substitution was carried out at position -R2, -R3, —R4 and —R5 after keeping hydroxyl group substitution static at position —R. When the substitution of —OH, -NH2 and —Cl group was done at —R2 position after keeping hydroxyl group substitution static at position —R then our results showed that substituted ligands are having better property as compared to our prototype Imatinib as shown in Table 1, 2, 3, 4 and 5.

But according to docking studies designed ligand which is substituted with hydroxyl and amine group IA-7 and IA-8 is showing approximately similar docking result as shown in Table 1.

protein structure activity relationship of imatinib

This resistance is usually due to protein is available in Protein Data Bank. The selected protein 3D structure is having 4 chains, hence only chain A was isolated In this study, Structure Activity Relationship from the structure and used for docking. Autodock uses binding with increased potency.

Whose activity and free energy evaluation to find the best binding efficiency has been proved by some Insilco tools mode. Autodock energy values were calculated by and internet JAVA based servers. Imatinib is a first energy, desolvation energy, and electrostatic generation therapeutic agent of BCR-ABL energyinternal energy of ligand, and torsional Tyrosine Kinase. It is generally used for treating free energy.

Analogues have been designed by taking Imatinib as a prototype.

Imatinib - DrugBank

Substitutions have been made by —OH, - NH2 and -Cl at position -R, -R1, -R2, -R3, —R4 and — R5 in such a way that binding energy, molecular properties Druglikeness score, Hydrogen bond donor, hydrogen bond acceptor etc and other pharmacological properties Absorption, Distribution, Metabolism, Excretion, Toxicity etc are higher than that of the prototype as discussed in FIG. Pictures have been taken from server http: OSIRIS property results showed that substituted ligands are having Explorer is also used to predict toxicity and other better pharmacological property as compared to drug like properties The metabolic sites of these Imatinib.

But the ligand which is substituted with designed drugs have been predicted using hydroxyl group IA-1 is showing best result as MetaPrint2D 18 as shown in Fig. Thus further substitution was carried server Ligands with substitution of —OH, -NH2 2.

But the ligand which is substituted with hydroxyl group IA-4 is showing better result as compared to amine and chloride substituted ligands IA-5 and IA-6 as shown in the Table 1, 2, 3, 4 and 5.

Thus further substitution was carried out at position -R2, -R3, —R4 and —R5 after keeping hydroxyl group substitution static at position —R. But the ligand which is substituted with amine group IA is showing better result as compared to hydroxyl and chloride substituted ligands IA and IA as shown in the Table 1, 2, 3, 4 and FIG.

Ligands with substitution of —OH, -NH2 results showed that substituted ligands are having and —Cl group at position — better property as compared to our prototype Imatinib as shown in Table 1, 2, 3, 4 and 5. But according to docking studies designed ligand which is substituted with hydroxyl and amine group IA-7 and IA-8 is showing approximately similar docking result as shown in Table 1. But both hydroxyl and amine substituted ligands has shown better result as compared to chloride substituted ligand IA On further examining the drug likeness property as calculated my molsoft server as shown in Table 2, amine substituted ligand IA- 8 was found to possess more druglikeness score as compared to hydroxyl group substituted ligand IA- R4: Thus further substitution was carried out at FIG.

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But out of all designed ligands, —R4 substituted ligands. But out of all designed chloride substituted ligand IA at position—R4 ligands, hydroxyl substituted ligand IA has has given the best result as shown in Table 1, 2, 3, given the best result as compared to different 4 and 5.

Thus further substitution was carried out substitutated ligands at position —R, -R1, -R2, -R3, — at position —R5 after keeping hydroxyl and amine R4 and —R5 with different functional group.

The molecular docking study of respectively to get more active and potent the designed ligands with Human Abl kinase molecule. Thus results predict that the designed ligands have the better binding affinity with BCR-Abl tyrosine kinase than Imatinib Table 1.

protein structure activity relationship of imatinib