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Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis.
J Med Chem. 2001 Nov 08; 44(23):3786-94.JM

Abstract

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme that has recently emerged as an important player in the mechanisms leading to postischemic neuronal death, and PARP inhibitors have been proposed as potential neuroprotective agents. With the aim of clarifying the structural basis responsible for PARP inhibition, we carried out a computational study on 46 inhibitors available through the literature. Our computational approach is composed of three parts. In the first one, representative PARP inhibitors have been docked into the crystallographic structure of the catalytic domain of PARP by using the Autodock 2.4 program. The docking studies thus carried out have provided an alignment scheme that has been instrumental for superimposing all the remaining inhibitors. Upon the basis of this alignment scheme, a quantitative structure-activity relationship (QSAR) analysis has been carried out after electrostatic and steric interaction energies have been computed with the RECEPTOR program. The QSAR analysis yielded a predictive model able to explain much of the variance of the 46-compound data set. The inspection of the QSAR coefficients revealed that the major driving force for potent inhibition is given by the extension of the contact surface between enzyme and inhibitors while electrostatic energy and hydrogen bonding capability play a minor role. Finally, the projection of the QSAR coefficients back onto the X-ray structure of the catalytic domain of PARP provides insights into the role played by specific amino acid residues. This information will be useful to address the design of new selective and potent PARP inhibitors.

Authors+Show Affiliations

Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06127 Perugia, Italy.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11689065

Citation

Costantino, G, et al. "Modeling of poly(ADP-ribose)polymerase (PARP) Inhibitors. Docking of Ligands and Quantitative Structure-activity Relationship Analysis." Journal of Medicinal Chemistry, vol. 44, no. 23, 2001, pp. 3786-94.
Costantino G, Macchiarulo A, Camaioni E, et al. Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. J Med Chem. 2001;44(23):3786-94.
Costantino, G., Macchiarulo, A., Camaioni, E., & Pellicciari, R. (2001). Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. Journal of Medicinal Chemistry, 44(23), 3786-94.
Costantino G, et al. Modeling of poly(ADP-ribose)polymerase (PARP) Inhibitors. Docking of Ligands and Quantitative Structure-activity Relationship Analysis. J Med Chem. 2001 Nov 8;44(23):3786-94. PubMed PMID: 11689065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis. AU - Costantino,G, AU - Macchiarulo,A, AU - Camaioni,E, AU - Pellicciari,R, PY - 2001/11/2/pubmed PY - 2002/1/5/medline PY - 2001/11/2/entrez SP - 3786 EP - 94 JF - Journal of medicinal chemistry JO - J Med Chem VL - 44 IS - 23 N2 - Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme that has recently emerged as an important player in the mechanisms leading to postischemic neuronal death, and PARP inhibitors have been proposed as potential neuroprotective agents. With the aim of clarifying the structural basis responsible for PARP inhibition, we carried out a computational study on 46 inhibitors available through the literature. Our computational approach is composed of three parts. In the first one, representative PARP inhibitors have been docked into the crystallographic structure of the catalytic domain of PARP by using the Autodock 2.4 program. The docking studies thus carried out have provided an alignment scheme that has been instrumental for superimposing all the remaining inhibitors. Upon the basis of this alignment scheme, a quantitative structure-activity relationship (QSAR) analysis has been carried out after electrostatic and steric interaction energies have been computed with the RECEPTOR program. The QSAR analysis yielded a predictive model able to explain much of the variance of the 46-compound data set. The inspection of the QSAR coefficients revealed that the major driving force for potent inhibition is given by the extension of the contact surface between enzyme and inhibitors while electrostatic energy and hydrogen bonding capability play a minor role. Finally, the projection of the QSAR coefficients back onto the X-ray structure of the catalytic domain of PARP provides insights into the role played by specific amino acid residues. This information will be useful to address the design of new selective and potent PARP inhibitors. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/11689065/Modeling_of_poly_ADP_ribose_polymerase__PARP__inhibitors__Docking_of_ligands_and_quantitative_structure_activity_relationship_analysis_ L2 - https://doi.org/10.1021/jm010116l DB - PRIME DP - Unbound Medicine ER -