title: Insight through molecular mechanics Poisson-Boltzmann surface area calculations into the binding affinity of triclosan and three analogues for FabI, the E. coli enoyl reductase.
abstract: Keeping pace with emerging drug resistance in clinically important pathogens will be greatly aided by inexpensive yet reliable computational methods that predict the binding affinities of ligands for drug targets. We present results using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method to calculate the affinity of a series of triclosan analogues for the E. coli enoyl reductase FabI, spanning a 450000-fold range of binding affinities. Significantly, a high correlation is observed between the calculated binding energies and those determined experimentally. Further examination indicates that the van der Waals energies are the most correlated component of the total affinity (r2 = 0.74), indicating that the shape of the inhibitor is very important in defining the binding energies for this system. The validation of MM-PBSA for the E coli FabI system serves as a platform for inhibitor design efforts focused on the homologous enzyme in Staphylococcus aureus and Mycobacterium tuberculosis.
authors.affiliation: Biochemistry and Structural Biology Graduate Program, Department of Chemistry, and Center for Structural Biology, Stony Brook University, New York 11794-5115, USA.
authors.forename: Salma B
authors.initials: SB
authors.lastname: Rafi
authors.forename: Guanglei
authors.initials: G
authors.lastname: Cui
authors.forename: Kun
authors.initials: K
authors.lastname: Song
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Cheng
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
mesh_terms: D001665:Binding Sites; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D054889:Fatty Acid Synthase, Type II; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics; D014260:Triclosan / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D029968:Escherichia coli Proteins; D009243:NAD; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C493924:fabI protein, E coli; D054889:Fatty Acid Synthase, Type II