Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule

Bellocchi, Daniele; Macchiarulo, Antonio; Costantino, Gabriele; Pellicciari, Roberto

doi:10.1016/j.bmc.2004.11.024

Cited by 53 publications

(28 citation statements)

References 22 publications

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“…Once there, they poly(ADP-ribosyl)ate target protein (s) to regulate transcription. The PARP catalytic domains of RCD1 and SRO1 retain several important conserved residues that are present in the human, murine, chicken, maize (Zea mays), and Arabidopsis PARPs (Ruf et al, 1996(Ruf et al, , 1998a(Ruf et al, , 1998bAme et al, 2004;Kinoshita et al, 2004;Oliver et al, 2004;Bellocchi et al, 2005). Importantly, the residues necessary to form the donor site (Gly-347, are present in the two proteins, as is the residue Tyr-378, necessary for forming the acceptor site (Ruf et al, 1996;Oliver et al, 2004).…”

Section: Genotypementioning

confidence: 99%

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

2009

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RADICAL-INDUCED CELL DEATH1 (RCD1) and SIMILAR TO RCD ONE1 (SRO1) are the only two proteins encoded in the Arabidopsis (Arabidopsis thaliana) genome containing both a putative poly(ADP-ribose) polymerase catalytic domain and a WWE protein-protein interaction domain, although similar proteins have been found in other eukaryotes. Poly(ADP-ribose) polymerases mediate the attachment of ADP-ribose units from donor NAD + molecules to target proteins and have been implicated in a number of processes, including DNA repair, apoptosis, transcription, and chromatin remodeling. We have isolated mutants in both RCD1 and SRO1, rcd1-3 and sro1-1, respectively. rcd1-3 plants display phenotypic defects as reported for previously isolated alleles, most notably reduced stature. In addition, rcd1-3 mutants display a number of additional developmental defects in root architecture and maintenance of reproductive development. While single mutant sro1-1 plants are relatively normal, loss of a single dose of SRO1 in the rcd1-3 background increases the severity of several developmental defects, implying that these genes do share some functions. However, rcd1-3 and sro1-1 mutants behave differently in several developmental events and abiotic stress responses, suggesting that they also have distinct functions. Remarkably, rcd1-3; sro1-1 double mutants display severe defects in embryogenesis and postembryonic development. This study shows that RCD1 and SRO1 are at least partially redundant and that they are essential genes for plant development.

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Section: Genotypementioning

confidence: 99%

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

2009

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“…Although the complete enzyme has not been crystallised, the crystal structure of the latter NAD + -binding catalytic domain of PARP-1 from chicken was reported in 1996 and the data were disclosed in 1997 [17]. This structure has been used extensively for the study of the catalytic mechanism of the enzyme [18], for the design of candidate inhibitors and for ex post facto rationalisation of the binding modes of inhibitors and of structure-activity relationships [19][20][21][22][23][24][25]. Scheme 1.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribose)polymerase Inhibition - Where Now?

Woon

Threadgill

2005

CMC

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The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD(+) to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD(+) and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through pro-drug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)-glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.

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“…The water molecule is not only involved in the hydrolysis mechanism of NAD + , but as we have already reported, is also involved in bond stability of PARP inhibitors; in fact, it should be considered part of their hydration shell. [15] These results suggest the potential success of new PARP inhibitors with a design based on transition-state structure.…”

Section: Discussionmentioning

confidence: 96%

“…First, this reaction can be taken as a model for the general nucleophilic attack reaction; second, the catalytically relevant water molecule may also play a role in determining the binding orientation of competitive PARP-1 inhibitors. [15] [a] Dr. D. Bellocchi Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which uses NAD + as substrate and catalyzes the transfer of multiple units of ADP-ribose to target proteins. PARP is an attractive target for the discovery of novel therapeutic agents and PARP inhibitors are currently evaluated for the treatment of a variety of pathological conditions such as brain ischemia, inflammation, and cancer.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP‐Ribose)‐Polymerase‐Catalyzed Hydrolysis of NAD⁺: QM/MM Simulation of the Enzyme Reaction

et al. 2006

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Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which uses NAD+ as substrate and catalyzes the transfer of multiple units of ADP-ribose to target proteins. PARP is an attractive target for the discovery of novel therapeutic agents and PARP inhibitors are currently evaluated for the treatment of a variety of pathological conditions such as brain ischemia, inflammation, and cancer. Herein, we use the PARP-catalyzed reaction of NAD+ hydrolysis as a model for gaining insight into the molecular details of the catalytic mechanism of PARP. The reaction has been studied in both the gas-phase and in the enzyme environment through a QM/MM approach. Our results indicate that the cleavage reaction of the nicotinamide-ribosyl bond proceeds through an SN2 dissociative mechanism via an oxacarbenium transition structure. These results confirm the importance of the structural water molecule in the active site and may constitute the basis for the design of transition-state-based PARP inhibitors.

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Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule

Cited by 53 publications

References 22 publications

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

Poly(ADP-ribose)polymerase Inhibition - Where Now?

Poly(ADP‐Ribose)‐Polymerase‐Catalyzed Hydrolysis of NAD⁺: QM/MM Simulation of the Enzyme Reaction

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Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule

Cited by 53 publications

References 22 publications

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

The Paralogous GenesRADICAL-INDUCED CELL DEATH1andSIMILAR TO RCD ONE1Have Partially Redundant Functions during Arabidopsis Development

Poly(ADP-ribose)polymerase Inhibition - Where Now?

Poly(ADP‐Ribose)‐Polymerase‐Catalyzed Hydrolysis of NAD+: QM/MM Simulation of the Enzyme Reaction

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Poly(ADP‐Ribose)‐Polymerase‐Catalyzed Hydrolysis of NAD⁺: QM/MM Simulation of the Enzyme Reaction