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Molecular docking studies of benzimidazopyrimidine and coumarin substituted benzimidazopyrimidine derivatives: As potential human Aurora A kinase inhibitors.

ABSTRACT: Protein kinases are important drug targets in human cancers, inflammation and metabolic diseases. Docking studies was performed for all the benzimidazopyrimidine and coumarin substituted benzimidazopyridimine derivatives with human Aurora A kinase target (3FDN) employing flexible ligand docking approach by using AutoDock 4.2. All the compounds were found to have minimum binding energy ranging from -6.26 to -9.29 kJ/mol. Among the molecules tested for docking study, 10-(6-Bromo-2-oxo- 2H-chromen-4-ylmethyl)-2-isopropyl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one (2k) showed minimum binding energy (-9.29 kJ/mol) with ligand efficiency of -0.31. All the ligands were docked deeply within the binding pocket region of 3FDN showing hydrogen bonds with Ala 213 and Asn 261. The docking study results showed that these derivatives are excellent inhibitor of human Aurora A kinase target; and also all these docked compounds have good inhibition constant, vdW + Hbond + desolv energy with best RMSD value.

SUBMITTER: Chandra

PROVIDER: S-EPMC4070038 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Molecular docking studies of benzimidazopyrimidine and coumarin substituted benzimidazopyrimidine derivatives: As potential human Aurora A kinase inhibitors.

Chandra Puttaraju Kallimeledoddi B KB Mahesh Sankanahally Srinivasshetty SS Shivashankar Kalegowda K Lokanath Neratur Krishnappagowda NK Madegowda Mahendra M

Bioinformation 20140520 5

Protein kinases are important drug targets in human cancers, inflammation and metabolic diseases. Docking studies was performed for all the benzimidazopyrimidine and coumarin substituted benzimidazopyridimine derivatives with human Aurora A kinase target (3FDN) employing flexible ligand docking approach by using AutoDock 4.2. All the compounds were found to have minimum binding energy ranging from -6.26 to -9.29 kJ/mol. Among the molecules tested for docking study, 10-(6-Bromo-2-oxo- 2H-chromen- ...[more]

PMID: 24966536

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Project description:The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure-activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson's electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, and 6a-e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (-9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.

Dataset Information

Molecular docking studies of benzimidazopyrimidine and coumarin substituted benzimidazopyrimidine derivatives: As potential human Aurora A kinase inhibitors.

Publications

Molecular docking studies of benzimidazopyrimidine and coumarin substituted benzimidazopyrimidine derivatives: As potential human Aurora A kinase inhibitors.

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