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A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study.
J Mol Graph Model. 2016 11; 70:54-69.JM

Abstract

Deregulated epigenetic activity of Histone deacetylase 1 (HDAC1) in tumor development and carcinogenesis pronounces it as promising therapeutic target for cancer treatment. HDAC1 has recently captured the attention of researchers owing to its decisive role in multiple types of cancer. In the present study a multistep framework combining ligand based 3D-QSAR, molecular docking and Molecular Dynamics (MD) simulation studies were performed to explore potential compound with good HDAC1 binding affinity. Four different pharmacophore hypotheses Hypo1 (AADR), Hypo2 (AAAH), Hypo3 (AAAR) and Hypo4 (ADDR) were obtained. The hypothesis Hypo1 (AADR) with two hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatics ring (R) was selected to build 3D-QSAR model on the basis of statistical parameter. The pharmacophore hypothesis produced a statistically significant QSAR model, with co-efficient of correlation r2=0.82 and cross validation correlation co-efficient q2=0.70. External validation result displays high predictive power with r2 (o) value of 0.88 and r2 (m) value of 0.58 to carry out further in silico studies. Virtual screening result shows ZINC70450932 as the most promising lead where HDAC1 interacts with residues Asp99, His178, Tyr204, Phe205 and Leu271 forming seven hydrogen bonds. A high docking score (-11.17kcal/mol) and lower docking energy -37.84kcal/mol) displays the binding efficiency of the ligand. Binding free energy calculation was done using MM/GBSA to access affinity of ligands towards protein. Density Functional Theory was employed to explore electronic features of the ligands describing intramolcular charge transfer reaction. Molecular dynamics simulation studies at 50ns display metal ion (Zn)-ligand interaction which is vital to inhibit the enzymatic activity of the protein.

Authors+Show Affiliations

Structural Biology and Bio-computing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630004 Tamil Nadu, India.Structural Biology and Bio-computing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630004 Tamil Nadu, India. Electronic address: jjkanthan@gmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27668885

Citation

Choubey, Sanjay K., and Jeyakanthan Jeyaraman. "A Mechanistic Approach to Explore Novel HDAC1 Inhibitor Using Pharmacophore Modeling, 3D- QSAR Analysis, Molecular Docking, Density Functional and Molecular Dynamics Simulation Study." Journal of Molecular Graphics & Modelling, vol. 70, 2016, pp. 54-69.
Choubey SK, Jeyaraman J. A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study. J Mol Graph Model. 2016;70:54-69.
Choubey, S. K., & Jeyaraman, J. (2016). A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study. Journal of Molecular Graphics & Modelling, 70, 54-69. https://doi.org/10.1016/j.jmgm.2016.09.008
Choubey SK, Jeyaraman J. A Mechanistic Approach to Explore Novel HDAC1 Inhibitor Using Pharmacophore Modeling, 3D- QSAR Analysis, Molecular Docking, Density Functional and Molecular Dynamics Simulation Study. J Mol Graph Model. 2016;70:54-69. PubMed PMID: 27668885.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study. AU - Choubey,Sanjay K, AU - Jeyaraman,Jeyakanthan, Y1 - 2016/09/14/ PY - 2016/05/21/received PY - 2016/09/10/revised PY - 2016/09/12/accepted PY - 2016/9/27/pubmed PY - 2018/1/30/medline PY - 2016/9/27/entrez KW - 3D-QSAR KW - Binding free energy KW - Density functional theory KW - Molecular docking KW - Molecular dynamics KW - Pharmacophore SP - 54 EP - 69 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 70 N2 - Deregulated epigenetic activity of Histone deacetylase 1 (HDAC1) in tumor development and carcinogenesis pronounces it as promising therapeutic target for cancer treatment. HDAC1 has recently captured the attention of researchers owing to its decisive role in multiple types of cancer. In the present study a multistep framework combining ligand based 3D-QSAR, molecular docking and Molecular Dynamics (MD) simulation studies were performed to explore potential compound with good HDAC1 binding affinity. Four different pharmacophore hypotheses Hypo1 (AADR), Hypo2 (AAAH), Hypo3 (AAAR) and Hypo4 (ADDR) were obtained. The hypothesis Hypo1 (AADR) with two hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatics ring (R) was selected to build 3D-QSAR model on the basis of statistical parameter. The pharmacophore hypothesis produced a statistically significant QSAR model, with co-efficient of correlation r2=0.82 and cross validation correlation co-efficient q2=0.70. External validation result displays high predictive power with r2 (o) value of 0.88 and r2 (m) value of 0.58 to carry out further in silico studies. Virtual screening result shows ZINC70450932 as the most promising lead where HDAC1 interacts with residues Asp99, His178, Tyr204, Phe205 and Leu271 forming seven hydrogen bonds. A high docking score (-11.17kcal/mol) and lower docking energy -37.84kcal/mol) displays the binding efficiency of the ligand. Binding free energy calculation was done using MM/GBSA to access affinity of ligands towards protein. Density Functional Theory was employed to explore electronic features of the ligands describing intramolcular charge transfer reaction. Molecular dynamics simulation studies at 50ns display metal ion (Zn)-ligand interaction which is vital to inhibit the enzymatic activity of the protein. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/27668885/A_mechanistic_approach_to_explore_novel_HDAC1_inhibitor_using_pharmacophore_modeling_3D__QSAR_analysis_molecular_docking_density_functional_and_molecular_dynamics_simulation_study_ DB - PRIME DP - Unbound Medicine ER -