A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus.
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.
a Departamento de Química Farmacológica y Toxicológica , Universidad de Chile , Santiago , Chile.
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Andrades
a Departamento de Química Farmacológica y Toxicológica , Universidad de Chile , Santiago , Chile.
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Campanini
a Departamento de Química Farmacológica y Toxicológica , Universidad de Chile , Santiago , Chile.
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D
Vásquez
b Department of Bioengineering , Imperial College London , London , England.
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Silvestri
c Departamento de Ciencias Químicas y Biológicas , Universidad Bernardo O Higgins , Santiago , Chile.
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C
Morales
d Department of Pharmacy , Pontificia Universidad Católica de Chile , Santiago , Chile.
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J
Romero
e Instituto de Química y Bioquímica, Universidad de Valparaíso , Valparaíso , Chile.
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J
Mella
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013211:Staphylococcus aureus / Q000187:drug effects*; D055672:Static Electricity
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001549:Benzamides; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D008024:Ligands
3D-QSAR; CoMFA; CoMSIA; FtsZ protein; antibacterial; benzamide