A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study.
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.
Structural Biology and Bio-computing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630004 Tamil Nadu, India.
Sanjay K
SK
Choubey
Structural Biology and Bio-computing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630004 Tamil Nadu, India. Electronic address: jjkanthan@gmail.com.
Jeyakanthan
J
Jeyaraman
D000595:Amino Acid Sequence; D004353:Drug Evaluation, Preclinical; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D012044:Regression Analysis; D015203:Reproducibility of Results; D016415:Sequence Alignment; D055672:Static Electricity; D013237:Stereoisomerism; D013816:Thermodynamics
D056572:Histone Deacetylase Inhibitors; D008024:Ligands; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
3D-QSAR; Binding free energy; Density functional theory; Molecular docking; Molecular dynamics; Pharmacophore