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Structure Based Drug Designing of Histone Deacetylase-2 inhibitors as an Anticancer Agents

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Title Statement Structure Based Drug Designing of Histone Deacetylase-2 inhibitors as an Anticancer Agents
 
Added Entry - Uncontrolled Name Bisht, Somya ; KUMAUN UNIVERSITY
Subbarao, Dr. Naidu ; School of computational and integrative sciences, JNU campus new delhi
Singh, Dr. Anita ; Department of pharmaceutical sciences bhimtal campus kumaun University Nainital
 
Summary, etc. <p id="docs-internal-guid-ed95dc1f-7fff-a43c-f754-e8a5bddc269c" dir="ltr"><span>Background and purpose-</span><span> Histone deacetylase 2 (HDAC2) in tumour development and carcinogenesis as a promising therapeutic target for cancer treatment. HDAC-2 belongs to class I histone deacetylase and acts as a transcriptional repressor through the deacetylation of lysine residues present at the N-terminal tail of histone proteins (H2A, H2B, H3 and H4). They are overexpressed in various solid tumours like cutaneous t cell lymphoma, colorectal, prostate cancer, lung cancer, breast cancer, gastric cancer, liver cancer and medulloblastoma. Hence, targeting HDAC-2 could be rewarding strategy to combat cancer.</span><span> </span><span>The goal of the research is to design, develop and identification of molecules through docking, Ligplot, ADMET properties and dynamic studies. </span></p><p dir="ltr"><span>Objective- To update HDAC-2 databases as a resource for Structure based drug designing. Validation of model by understanding the interaction pattern with known inhibitors. To identify selective and trapping HDAC-2 inhibitors by targeting the catalytic domain through structure-based pharmacophore study. To design novel HDAC inhibitors (HDACi) analogues for further generation of new compounds through software. Molecular dynamics simulations for most active compound.</span></p><p dir="ltr"><span>Methods- In the present study HDAC-2 protein (PDB-4LY1) from RCSB PDB screened and retrieved. The different set of data for ligand preparation were downloaded from CHEMBL, NCI, Anticancer databases and FDA approved drugs of HDACi were downloaded from PubChem. The compounds were screened with two software Schrodinger and gold. The multiset framework combining ligand preparation, protein preparation, grid generation, ADMET prediction, molecular docking, Ligplot analysis and molecular dynamics (MD) simulation studies was performed to find the potential compound with HDAC-2 binding affinity.</span></p><p dir="ltr"><span>Result- The optimised compound shows high docking score from ChEMBL (-14.078) and NCI library it shows (-12.083) as compared to reference drug Panobinostat (-9.157).  binding energy, hydrogen bonding and hydrophobic interaction against the reference compound. 20 compounds were selected as the best HDAC2 inhibitors based on the glide score, binding energy, hydrogen bonding, hydrophobic interaction. Top two compound show Ligplot analysis. Then the one highest docked compound shows dynamic study at 50ns shows binding stability with the inhibitor. Finally find its ADMET property.</span></p><p dir="ltr"><span>Conclusion- The virtual screening of drugs through software is ongoing process and 20 modified analogues those which satisfied all the screening results have been found to be better than the conventional drugs available. Further, synthesis, in vivo and cytotoxic studies of synthesised molecules are under process.</span></p><p dir="ltr"><span>KEYWORDS- Histone acetylase, histone deacetylase, histone deacetylase-2, molecular dynamics, 4LY1, ADME property, histone deacetylase inhibitor, Optimized Potential for Liquid Simulation 3e, high throughput virtual screening, standard precision, extra precision.</span></p>
 
Publication, Distribution, Etc. Indian Journal of Chemistry (IJC)
2022-09-20 12:49:50
 
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http://op.niscair.res.in/index.php/IJC/article/view/60668
 
Data Source Entry Indian Journal of Chemistry (IJC); ##issue.vol## 61, ##issue.no## 9 (2022): Indian Journal of Chemistry-(IJC)
 
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Nonspecific Relationship Entry http://op.niscair.res.in/index.php/IJC/article/download/60668/465604729
http://op.niscair.res.in/index.php/IJC/article/download/60668/465604730
http://op.niscair.res.in/index.php/IJC/article/download/60668/465612747
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http://op.niscair.res.in/index.php/IJC/article/download/60668/465616406
http://op.niscair.res.in/index.php/IJC/article/download/60668/465616407
http://op.niscair.res.in/index.php/IJC/article/download/60668/465616527