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A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus.
SAR QSAR Environ Res. 2015; 26(11):925-42.SQ

Abstract

A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure-activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r(2)(pred) = 0.974) and CoMSIA (r(2)(pred) = 0.980) analyses.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Andrades J
a Departamento de Química Farmacológica y Toxicológica , Universidad de Chile , Santiago , Chile.
Campanini J
a Departamento de Química Farmacológica y Toxicológica , Universidad de Chile , Santiago , Chile.
Vásquez D
a Departamento de Química Farmacológica y Toxicológica , Universidad de Chile , Santiago , Chile.
Silvestri C
b Department of Bioengineering , Imperial College London , London , England.
Morales C
c Departamento de Ciencias Químicas y Biológicas , Universidad Bernardo O Higgins , Santiago , Chile.
Romero J
d Department of Pharmacy , Pontificia Universidad Católica de Chile , Santiago , Chile.
Mella J
e Instituto de Química y Bioquímica, Universidad de Valparaíso , Valparaíso , Chile.

MeSH

Anti-Bacterial AgentsBacterial ProteinsBenzamidesCytoskeletal ProteinsDrug DesignDrug Resistance, BacterialHydrogen BondingHydrophobic and Hydrophilic InteractionsLigandsModels, MolecularQuantitative Structure-Activity RelationshipStaphylococcus aureusStatic Electricity

Pub Type(s)

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

Language

eng

PubMed ID

26505124

Citation

Andrades, J, et al. "A Combined CoMFA and CoMSIA 3D-QSAR Study of Benzamide Type Antibacterial Inhibitors of the FtsZ Protein in Drug-resistant Staphylococcus Aureus." SAR and QSAR in Environmental Research, vol. 26, no. 11, 2015, pp. 925-42.
Andrades J, Campanini J, Vásquez D, et al. A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus. SAR QSAR Environ Res. 2015;26(11):925-42.
Andrades, J., Campanini, J., Vásquez, D., Silvestri, C., Morales, C., Romero, J., & Mella, J. (2015). A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus. SAR and QSAR in Environmental Research, 26(11), 925-42. https://doi.org/10.1080/1062936X.2015.1095798
Andrades J, et al. A Combined CoMFA and CoMSIA 3D-QSAR Study of Benzamide Type Antibacterial Inhibitors of the FtsZ Protein in Drug-resistant Staphylococcus Aureus. SAR QSAR Environ Res. 2015;26(11):925-42. PubMed PMID: 26505124.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus. AU - Andrades,J, AU - Campanini,J, AU - Vásquez,D, AU - Silvestri,C, AU - Morales,C, AU - Romero,J, AU - Mella,J, Y1 - 2015/10/27/ PY - 2015/10/28/entrez PY - 2015/10/28/pubmed PY - 2016/8/2/medline KW - 3D-QSAR KW - CoMFA KW - CoMSIA KW - FtsZ protein KW - antibacterial KW - benzamide SP - 925 EP - 42 JF - SAR and QSAR in environmental research JO - SAR QSAR Environ Res VL - 26 IS - 11 N2 - A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure-activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r(2)(pred) = 0.974) and CoMSIA (r(2)(pred) = 0.980) analyses. SN - 1029-046X UR - https://www.unboundmedicine.com/medline/citation/26505124/A_combined_CoMFA_and_CoMSIA_3D_QSAR_study_of_benzamide_type_antibacterial_inhibitors_of_the_FtsZ_protein_in_drug_resistant_Staphylococcus_aureus_ DB - PRIME DP - Unbound Medicine ER -