title: Investigating the allosteric reverse signalling of PARP inhibitors with microsecond molecular dynamic simulations and fluorescence anisotropy.
abstract: The inhibition of the poly(ADP-ribose) polymerase (PARP) family members is a strategy pursued for the development of novel therapeutic agents in a range of diseases, including stroke, cardiac ischemia, cancer, inflammation and diabetes. Even though some PARP-1 inhibitors have advanced to clinical setting for cancer therapy, a great deal of attention is being devoted to understand the polypharmacology of current PARP inhibitors. Besides blocking the catalytic activity, recent works have shown that some PARP inhibitors exhibit a poisoning activity, by trapping the enzyme at damaged sites of DNA and forming cytotoxic complexes. In this study we have used microsecond molecular dynamics to study the allosteric reverse signalling that is at the basis of such an effect. We show that Olaparib, but not Veliparib and HYDAMTIQ, is able to induce a specific conformational drift of the WGR domain of PARP-1, which stabilizes PARP-1/DNA complex through the locking of several salt bridge interactions. Fluorescence anisotropy assays support such a mechanism, providing the first experimental evidence that HYDAMTIQ, a potent PARP inhibitor with neuroprotective properties, is less potent than Olaparib to trap PARP-1/DNA complex.
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, 06123 Perugia, Italy.
authors: Jean-Rémy
authors: JR
authors: Marchand
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, 06123 Perugia, Italy.
authors: Andrea
authors: A
authors: Carotti
authors: TES Pharma S.r.l. via Palmiro Togliatti 22bis 06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors: Daniela
authors: D
authors: Passeri
authors: TES Pharma S.r.l. via Palmiro Togliatti 22bis 06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors: Paolo
authors: P
authors: Filipponi
authors: TES Pharma S.r.l. via Palmiro Togliatti 22bis 06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors: Paride
authors: P
authors: Liscio
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, 06123 Perugia, Italy.
authors: Emidio
authors: E
authors: Camaioni
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, 06123 Perugia, Italy; TES Pharma S.r.l. via Palmiro Togliatti 22bis 06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors: Roberto
authors: R
authors: Pellicciari
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, 06123 Perugia, Italy.
authors: Antimo
authors: A
authors: Gioiello
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, 06123 Perugia, Italy. Electronic address: antonio.macchiarulo@unipg.it.
authors: Antonio
authors: A
authors: Macchiarulo
keywords: Cancer; Fluorescence anisotropy; Molecular dynamics; Neuroprotection; PARP; Polypharmacology