Research Article | Volume: 7, Issue: 1, January, 2017

In silico ADME/T and 3D QSAR analysis of KDR inhibitors

S. M. Zahid Hosen,  Raju Dash,  Mahmuda Khatun,  Rasheda Akter,  Md. Habibur Rahman Bhuiyan,  Md. Rezaul Karim,  Nusrat Jahan Mouri,  Forkan Ahamed,  Kazi Saiful Islam,  Sadia Afrin   
S. M. Zahid Hosen1, Raju Dash1, Mahmuda Khatun1, Rasheda Akter1, Md. Habibur Rahman Bhuiyan2, Md. Rezaul Karim3, Nusrat Jahan Mouri4, Forkan Ahamed5, Kazi Saiful Islam6, Sadia Afrin7

1Molecular Modeling & Drug Design Laboratory (MMDDL), Pharmacology Research Division, Bangladesh Council of Scientific & Industrial Research (BCSIR), Chittagong-4220, Bangladesh.

2Industrial Microbiology Research Division, Bangladesh Council of Scientific & Industrial Research (BCSIR), Chittagong-4220, Bangladesh.

3Institute of Food Science & Technology (IFST), BCSIR, Dhaka.

4Industrial Botany Research Division, Bangladesh Council of Scientific & Industrial Research (BCSIR), Chittagong-4220, Bangladesh.

5Department of Microbiology, Faculty of Biological Science, University of Chittagong, Chittagong, Bangladesh. ​​​​​​

6Charles Perkins Center-University of Sydney, NSW 2050, Australia.

7Department of Nutritional Biochemistry, ICDDR, B, Dhaka 1212, Bangladesh.

Open Access   

Published:  Jan 31, 2017

DOI: 10.7324/JAPS.2017.70116
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Abstract

Tyrosine kinases (KDR) have been considered as a potential targets for the design of new anticancer agents. Recently, a series of N-4-chlorophenylnaphthamides has been reported with KDR inhibitory activity. In order to demonstrate the pharmacokinetics and the relationship between the structures and their inhibition of KDR, 3D-QSAR and in silico ADME/T analysis were performed on a dataset of 13 compounds. Quantum chemical parameters such as LUMO energy, HOMO energy, ionization energy (I), electron affinity (A), chemical potential (μ), hardness (η) and electrophilicity (χ) of the compounds are calculated by using semi-empirical SCF-MO method at PM3 level of theory and various SlogP descriptors from MOE software. In silico ADME/T analysis was performed by using different software’s Discovery Studio 2.5, TOPKAT and QikProp 4.3. From in silico ADME and Toxicity studies, it was revealed that selected derivatives have good oral absorption rate and metabolism with no BBB penetration. QSTR (Quantitative Structure Toxicity Relationship) studies by using TOPAK in various computational animal models, showed high LD50 values and the compounds are found to be noncarcenogenic. Moreover, three different QSAR models were generated by Partial Least Squares (PLS) Regression method having correlation coefficient (Q2) of 0.86382, 0.84372, and 0.82629, respectively. These models conclude a significant relationship of KDR inhibition with dipole moment (D), LUMO energy (ELUMO), hardness (η) and electrophilicity (χ), and hydrophobicity of compounds, regarding N-4-chlorophenylnaphthamides.


Keyword:     N-4-chlorophenylnaphthamides QSAR QSTR HUMO LUMO LD50 KDR.

Citation:

Hosen SMZ, Dash R, Khatun M, Akter R, Bhuiyan MHR, Karim MR, Mouri NJ, Ahmed F, Islam KS, Afrin S. In silico ADME/T and 3D QSAR analysis of KDR inhibitors. J App Pharm Sci, 2017; 7 (01): 120-128.

Copyright:The Author(s). This is an open access article distributed under the Creative Commons Attribution Non-Commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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