Dihydropteroate synthase (DHPS) is an alluring target for designing novel drug candidates to prevent
infections caused by pathogenic Escherichia coli strains. Diaryl
Sulfone (SO) compounds are found to inhibit DHPS competitively with respect to the substrate
pABA (
p-aminobenzoate). The extra aromatic ring of diaryl
sulfone compounds found to stabilize them in highly flexible
pABA binding loops. In this present study, a statistically significant 3D-QSAR model was developed using a data set of diaryl
sulfone compounds. The favourable and unfavourable contributions of substitutions in
sulfone compounds were illustrated by contour plot obtained from the developed 3D-QSAR model. Molecular docking calculations were performed to investigate the putative binding mode of diaryl
sulfone compounds at the catalytic pocket. DFT calculations were carried out using SCF approach, B3LYP- 6-31 G (d) basis set to compute the HOMO, LUMO energies and their respective location at
pABA binding pocket. Further, the developed model was validated by
FEP (Free Energy Perturbation) calculations. The calculated relative free energy of binding between the highly potent and less potent
sulfone compound was found to be -3.78 kcal/ mol which is comparable to the experimental value of -5.85 kcal/mol. A 10 ns molecular dynamics simulation of inhibitor and DHPS confirmed its stability at
pABA catalytic site. Outcomes of the present work provide deeper insight in designing novel drug candidates for pathogenic Escherichia coli strains.