Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validated in silico modeling techniques and molecular dynamics simulation
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validated in silico modeling techniques and molecular dynamics simulation
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| Creator |
Halder, Amit K
Saha, Achintya Das Saha, Krishna Jha, Tarun |
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| Subject |
Cancer Biology and Inflammatory Disorder Division
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| Description |
Inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) enzyme are useful for the treatment of various diseases
including cancer. Comparative in silico studies were performed on different ligand-based (2D-QSAR, Kernel-based
partial least square (KPLS) analysis, Pharmacophore Search Engine (PHASE) pharmacophore mapping), and structurebased
(molecular docking, MM-GBSA analyses, Gaussian-based 3D-QSAR analyses on docked poses) modeling techniques to explore the structure–activity relationship of a diverse set of PARP-1 inhibitors. Two-dimensional (2D)-QSAR
highlighted the importance of charge topological index (JGI7), fractional polar surface area (JursFPSA3), and connectivity index (CIC2) along with different molecular fragments. Favorable and unfavorable fingerprints were demonstrated in KPLS analysis, whereas important pharmacophore features (one acceptor, one donor, and two ring aromatic) along with favorable and unfavorable field effects were demonstrated in PHASE-based pharmacophore model. MM-GBSA analyses revealed significance of different polar, non-polar, and solvation energies. Docking-based alignment of ligands was used to perform Gaussian-based 3D-QSAR study that further demonstrated importance of different field effects. Overall, it was found that polar interactions (hydrogen bonding, bridged hydrogen bonding, and pi–cation) play major roles for higher activity. Steric groups increase the total contact surface area but it should have higher fractional polar surface area
to adjust solvation energy. Structure-based pharmacophore mapping spotted the positive ionizable feature of ligands as
the most important feature for discriminating highly active compounds from inactives. Molecular dynamics simulation,
conducted on highly active ligands, described the dynamic behaviors of the protein complexes and supported the interpretations obtained from other modeling analyses. The current study may be useful for designing PARP-1 inhibitors.
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| Date |
2015
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2223/1/JOURNAL_OF_BIOMOLECULAR_STRUCTURE_%26_DYNAMICS__V._33__(_8)1756%2D1779__2015[1].pdf
Halder, Amit K and Saha, Achintya and Das Saha, Krishna and Jha, Tarun (2015) Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validated in silico modeling techniques and molecular dynamics simulation. Journal of Biomolecular Structure and Dynamics, 33 (8). pp. 1756-1779. |
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| Relation |
http://dx.doi.org/10.1080/07391102.2014.969772
http://www.eprints.iicb.res.in/2223/ |
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