Rational questing for potential novel inhibitors of FabK from Streptococcus pneumoniae by combining FMO calculation, CoMFA 3D-QSAR modeling and virtual screening.
Enoyl-acyl carrier protein (ACP) reductase (ENR) is an attractive and potential target for developing selective antibacterial agents. Recent studies showed that FabK is the sole isoform of ENR in Streptococcus pneumoniae, and at the same time an X-ray crystallographic study of FabK from S. pneumoniae (SpFabK) was reported for the first time. Based on above information, the interaction mechanism and pair interaction energies between ligand and the active site of SpFabK were analyzed with the ab initio fragment molecular orbital (FMO) calculation based on the FlexX docking model at the FMO-RHF/6-31G* level. Subsequently, the first molecular docking-based 3D-QSAR model with comparative molecular field analysis (CoMFA) was established with cross-validated coefficients (q(2)) up to 0.511 and regression coefficients (r(2)) up to 0.986. Then integrating the 3D-QSAR CoMFA predicted model, molecular docking, and FMO pair interaction analysis structure-based virtual screening was performed, six novel and potential lead compounds were sorted out for further study.
Zhang
Qingye
Q
State Key Laboratory for Agricultural Microbiology and National Engineering Research Centre of Microbial Pesticides, Huazhong Agricultural University, Wuhan, People's Republic of China.
Yu
Chan
C
Min
Jun
J
Wang
Yan
Y
He
Jin
J
Yu
Ziniu
Z
D000465:Algorithms; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D004563:Electrochemistry; D004583:Electrons; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013499:Surface Properties; D013816:Thermodynamics
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)