Tags

Type your tag names separated by a space and hit enter

Binding mode of novel 1-substituted quinazoline derivatives to poly(ADP-ribose) polymerase-catalytic domain, revealed by X-ray crystal structure analysis of complexes.
Biochim Biophys Acta. 2006 May; 1764(5):913-9.BB

Abstract

In order to clarify the role of the 1-substituent of quinazoline derivatives in their inhibitory activity against poly(ADP-ribose) polymerase (PARP), two novel inhibitors, 1 [8-hydroxy-1-(3-morpholinopropyl)-quinazoline-2,4(1H,3H)-dione] and 2 [8-hydroxy-1-(3-phenoxypropyl)-quinazoline-2,4(1H,3H)-dione], were synthesized and subjected to X-ray crystal analysis in complex with the PARP C-terminal catalytic domain (PARP-CD), which requires NAD+ coenzyme for biological function. The nicotinamide-mimicking part of the quinazoline skeleton of 1 and 2 were both located at the nicotinamide subsite of the NAD+-binding pocket in the same manner as previously reported inhibitors: three hydrogen bonds [(Gly-863)NH-O12, (Gly-863)O-HN3 and (Ser-904)O(gamma)-O12] and stacking interaction between the Tyr-907 phenol and the quinazoline ring. On the other hand, the N-morpholinoprop-3-yl moiety introduced at the 1-position of the quinazoline ring in 1 bridged the large gap between the donor site and the acceptor site through a (Met-890)NH-O20(morpholine) hydrogen bond, where the donor and the acceptor sites are classified as the binding sites of NAD+ and the ADP moiety of the poly(ADP-ribose) chain, respectively. In contrast, the N-phenoxyprop-3-yl moiety in 2 formed hydrophobic interactions close to the adenosine-binding site of NAD+, unlike the hydrogen bond such as in 1. As the inhibitory activities of 1 and 2 for PARP were much more potent than those of the unsubstituted nicotinamide analogues, these results suggest that the occupation of the proximal region of the ADP phosphate-and adenosine-binding subsite of the donor site or that of the gap between the donor and the acceptor site by the 1-substituent of quinazoline may increase the inhibitory activity considerably. The nearly equal inhibitory activities of 1 and 2, despite of their different binding modes at the active site, indicate that this 1-substituent is promising in improving the bioavailability of the inhibitor without compromising its inhibitory activity.

Authors+Show Affiliations

Matsumoto K
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama 331-9530, Japan. k.matsumoto@po.rd.taisho.co.jp
Kondo K
No affiliation info available
Ota T
No affiliation info available
Kawashima A
No affiliation info available
Kitamura K
No affiliation info available
Ishida T
No affiliation info available

MeSH

AnimalsCatalytic DomainChickensCrystallography, X-RayPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesProtein BindingQuinazolines

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16631419

Citation

Matsumoto, Keita, et al. "Binding Mode of Novel 1-substituted Quinazoline Derivatives to poly(ADP-ribose) Polymerase-catalytic Domain, Revealed By X-ray Crystal Structure Analysis of Complexes." Biochimica Et Biophysica Acta, vol. 1764, no. 5, 2006, pp. 913-9.
Matsumoto K, Kondo K, Ota T, et al. Binding mode of novel 1-substituted quinazoline derivatives to poly(ADP-ribose) polymerase-catalytic domain, revealed by X-ray crystal structure analysis of complexes. Biochim Biophys Acta. 2006;1764(5):913-9.
Matsumoto, K., Kondo, K., Ota, T., Kawashima, A., Kitamura, K., & Ishida, T. (2006). Binding mode of novel 1-substituted quinazoline derivatives to poly(ADP-ribose) polymerase-catalytic domain, revealed by X-ray crystal structure analysis of complexes. Biochimica Et Biophysica Acta, 1764(5), 913-9.
Matsumoto K, et al. Binding Mode of Novel 1-substituted Quinazoline Derivatives to poly(ADP-ribose) Polymerase-catalytic Domain, Revealed By X-ray Crystal Structure Analysis of Complexes. Biochim Biophys Acta. 2006;1764(5):913-9. PubMed PMID: 16631419.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Binding mode of novel 1-substituted quinazoline derivatives to poly(ADP-ribose) polymerase-catalytic domain, revealed by X-ray crystal structure analysis of complexes. AU - Matsumoto,Keita, AU - Kondo,Kazuyuki, AU - Ota,Tomomi, AU - Kawashima,Akira, AU - Kitamura,Kunihiro, AU - Ishida,Toshimasa, Y1 - 2006/04/03/ PY - 2005/12/09/received PY - 2006/03/08/revised PY - 2006/03/14/accepted PY - 2006/4/25/pubmed PY - 2006/7/22/medline PY - 2006/4/25/entrez SP - 913 EP - 9 JF - Biochimica et biophysica acta JO - Biochim Biophys Acta VL - 1764 IS - 5 N2 - In order to clarify the role of the 1-substituent of quinazoline derivatives in their inhibitory activity against poly(ADP-ribose) polymerase (PARP), two novel inhibitors, 1 [8-hydroxy-1-(3-morpholinopropyl)-quinazoline-2,4(1H,3H)-dione] and 2 [8-hydroxy-1-(3-phenoxypropyl)-quinazoline-2,4(1H,3H)-dione], were synthesized and subjected to X-ray crystal analysis in complex with the PARP C-terminal catalytic domain (PARP-CD), which requires NAD+ coenzyme for biological function. The nicotinamide-mimicking part of the quinazoline skeleton of 1 and 2 were both located at the nicotinamide subsite of the NAD+-binding pocket in the same manner as previously reported inhibitors: three hydrogen bonds [(Gly-863)NH-O12, (Gly-863)O-HN3 and (Ser-904)O(gamma)-O12] and stacking interaction between the Tyr-907 phenol and the quinazoline ring. On the other hand, the N-morpholinoprop-3-yl moiety introduced at the 1-position of the quinazoline ring in 1 bridged the large gap between the donor site and the acceptor site through a (Met-890)NH-O20(morpholine) hydrogen bond, where the donor and the acceptor sites are classified as the binding sites of NAD+ and the ADP moiety of the poly(ADP-ribose) chain, respectively. In contrast, the N-phenoxyprop-3-yl moiety in 2 formed hydrophobic interactions close to the adenosine-binding site of NAD+, unlike the hydrogen bond such as in 1. As the inhibitory activities of 1 and 2 for PARP were much more potent than those of the unsubstituted nicotinamide analogues, these results suggest that the occupation of the proximal region of the ADP phosphate-and adenosine-binding subsite of the donor site or that of the gap between the donor and the acceptor site by the 1-substituent of quinazoline may increase the inhibitory activity considerably. The nearly equal inhibitory activities of 1 and 2, despite of their different binding modes at the active site, indicate that this 1-substituent is promising in improving the bioavailability of the inhibitor without compromising its inhibitory activity. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/16631419/Binding_mode_of_novel_1_substituted_quinazoline_derivatives_to_poly_ADP_ribose__polymerase_catalytic_domain_revealed_by_X_ray_crystal_structure_analysis_of_complexes_ DB - PRIME DP - Unbound Medicine ER -