Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validatedin silico modeling techniques and molecular dynamics simulation

Abstract

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 structure-based (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.

Anticancer effects of 10-hydroxycamptothecin induce apoptosis of human osteosarcoma through activating caspase-3, p53 and cytochrome�c pathways

“…Currently, increased expression of PARP-1 has been observed in multiple malignant types of tumor, including human osteosarcoma cells (20). As PARP-1 participates in DNA damage repair, the single application of a PARP-1 inhibitor treatment or a DNA damage drug combination may promote apoptosis (21). A previous study has demonstrated that drug inhibition or gene knockout PARP-1 may not only cause the avoidance of tissue damage caused by oxidative stress, but may also improve the prognosis of patients with cancer (22).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…Computational approaches have also been employed. Novel inhibitor scaffolds have been revealed by strategies including docking, active-site fingerprinting, and molecular dynamics (MD) simulations incorporating pharmacophore modeling to account for the dynamics of the potential inhibitors in the binding site (629)(630)(631)(632)(633)(634). There are also new inhibitor therapies for use as single or combination therapy being developed by both synthesis and modification of existing inhibitors (635).…”

Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di‐Substituted Oxadiazole‐Based Dibenzo‐Azepine‐Dione Derivatives on Poly (ADP‐Ribose) Polymerase‐1

“…Previous works on PARP‐1 MD simulations reported the involvement of polar interactions (hydrogen bonding and pi‐cation) and non‐polar interaction (Pi‐stacking) playing crucial roles in the higher activity of ligands in the active site of PARP‐1. Also, previous works described the involvement of van der Waals and hydrophobic interactions in the ligand‐PARP‐1 activities [11,17–19] . Findings from the current study may provide useful insights for the future rational design of novel PARP‐1 inhibitors for the treatment of cancer disease.…”

“…The poly (ADP) ribose polymers recruit other enzymes required for the repair of DNA. The indispensable role of PARP‐1 in the repair of single‐strand DNA lesions has made PARP‐1 a target in anticancer therapy [11] . Inhibitors of PARP‐1 are promising candidates for anticancer treatments [12] .…”