Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) polymerase 1 (PARP-1) is a key DNA repair enzyme and an important target in cancer treatment. Conventional methods of studying the reaction mechanism of PARP-1 have limitations because of the complex structure of PARP-1 substrates; however, the necessary data can be obtained by molecular modeling. In this work, a molecular dynamics model for the PARP-1 enzyme-substrate complex containing NAD+ molecule and the end of the poly(ADP-ribose) chain in the form of ADP molecule was obtained for the first time. Interactions with the active site residues have been characterized where Gly863, Lys903, Glu988 play a crucial role, and the SN1-like mechanism for the enzymatic ADP-ribosylation reaction has been proposed. Models of PARP-1 complexes with more sophisticated two-unit fragments of the growing polymer chain as well as competitive inhibitors 3-aminobenzamide and 7-methylguanine have been obtained by molecular docking.
 ...
PMID:Modeling of the Enzyme-Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1. 3207 21

The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCAmut breast and ovarian cancers has led to its exploitation as a target. The overexpression of PARP1 in several types of cancer further evoked interest in its use as an imaging target. While PARP1-targeted inhibitors have fast developed and approved in this past decade, determination of PARP1 expression might help to predict the response to PARP inhibitor treatment. This has the potential of improving prognosis and moving towards tailored therapy options and/or dosages. This review summarizes the recent pre-clinical advancements in imaging and theranostic PARP1 targeted tracers. To assess PARP1 levels, several imaging probes with fluorescent or beta/gamma emitting radionuclides have been proposed and three have advanced to ongoing clinical evaluation. Apart from its diagnostic value in detection of primary tumors as well as metastases, this shall also help in delivering therapeutic radionuclides to PARP1 overexpressing tumors. Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy.
 ...
PMID:Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes. 3264 Jul 8


<< Previous 1 2 3 4 5 6