Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A small agonistic peptide FRAP-4 (WEWT, Fas reactive peptide-4) that binds to the human Fas molecule was discovered using our computer screening strategy named the Amino acid Complement Wave (ACW) method, which is based on the complementarities of interacting amino acids between comprehensive testing peptides and a target protein surface pocket. In silico docking studies demonstrated the specific interaction of FRAP-4 with the main Fas ligand (FasL) binding domain in the Fas molecule. An octamer of this peptide produced by carboxyl terminal linkages of polylysine branches (MAP), (FRAP-4)8-MAP, effectively induced apoptosis in human ovarian cancer cell line NOS4 cells that was associated with the activation of caspases-8, -9 and -3, and the cleavage of PARP. Alanine substitution of the N-terminal W in FRAP-4 resulted in complete loss of FasL-mimetic action of (FRAP-4)8-MAP, suggesting that the aromatic functionality at the N-terminal position W appears to play an essentially important role in Fas binding ability. These observations indicate that the FasL-mimetic peptide should serve as an excellent starting point for the design of effective compounds with FasL-mimetic activity. Furthermore, the ACW method for the structure-based design of optimized small peptides against receptor molecules such as Fas could open new avenues for the development of peptide mimetic and nonpeptidic organic forms to generate novel effective pharmaceuticals.
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PMID:Structure-based design of an agonistic peptide targeting Fas. 1584 93

Selective poly (ADP-ribose) polymerase (PARP)-1 inhibitor represents promising therapy against cancers with a good balance between efficacy and safety. Owing to the conserved structure between PARP-1 and PARP-2, most of the clinical and experimental drugs show equivalent inhibition against both targets. Most recently, it's disclosed a highly selective PARP-1 inhibitor (NMS-P118) with promising pharmacokinetic properties. Herein, we combined molecular simulation with free energy calculation to gain insights into the selective mechanism of NMS-P118. Our results suggest the reduction of binding affinity for PARP-2 is attributed to the unfavorable conformational change of protein, which is accompanied by a significant energy penalty. Alanine-scanning mutagenesis study further reveals the important role for a tyrosine residue of donor loop (Tyr889(PARP-1) and Tyr455(PARP-2)) in contributing to the ligand selectivity. Retrospective structural analysis indicates the ligand-induced movement of Tyr455(PARP-2) disrupts the intra-molecule hydrogen bonding network, which partially accounts for the "high-energy" protein conformation in the presence of NMS-P118. Interestingly, such effect isn't observed in other non-selective PARP inhibitors including BMN673 and A861695, which validates the computational prediction. Our work provides energetic insight into the subtle variations in the crystal structures and could facilitate rational design of new selective PARP inhibitor.
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PMID:Free energy calculation provides insight into the action mechanism of selective PARP-1 inhibitor. 2696 80

The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have been proven effective to potentiate both chemotherapeutic agents and radiotherapy. However, a major problem of most current PARP inhibitors is their lack of selectivity for PARP-1 and its closest isoform PARP-2. NMS-P118 is a highly selective PARP inhibitor that binds PARP-1 stronger than PARP-2 and has many advantages such as excellent pharmacokinetic profiles. In this study, molecular dynamics (MD) simulations of NMS-P118 in complex with PARP-1 and PARP-2 were performed to understand the molecular mechanism of its selectivity. Alanine scanning together with free energy calculation using MM/GBSA and interaction entropy reveal key residues that are responsible for the selectivity. Although the conformation of the binding pockets and NMS-P118 are very similar in PARP-1 and PARP-2, most of the hot-spot residues in PARP-1 have stronger binding free energy than the corresponding residues in PARP-2. Detailed analysis of the binding energy shows that the 4'4-difluorocyclohexyl ring on NMS-P118 form favorable hydrophobic interaction with Y889 in PARP-1. In addition, the H862 residue in PARP-1 has stronger binding free energy than H428 in PARP-2, which is due to shorter distance and stronger hydrogen bonds. Moreover, the negatively charged E763 residue in PARP-1 forms stronger electrostatic interaction energy with the positively charged NMS-P118 than the Q332 residue in PARP-2. These results rationalize the selectivity of NMS-P118 and may be useful for designing novel selective PARP inhibitors.
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PMID:Molecular Mechanism of Selective Binding of NMS-P118 to PARP-1 and PARP-2: A Computational Perspective. 3237 27