Computer-assisted Design of Novel Polyketide Synthase 13 of Mycobacterium tuberculosis Inhibitors Using Molecular Modeling and Virtual Screening

Aims: Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids biosynthesis pathway Mycobacterium tuberculosis (Mtb). Therefore, Pks13 a promising drug target for treatment. Here we report silico design and evaluation novel inhibitors made benzofuran derivatives with favorable predicted pharmacokinetic profiles.
 Methodology: A 3D model Pks13-TAMx complexes was prepared training set 18 TAMs experimentally determined inhibitory potencies (half-maximal concentrations ) by using situ modifications crystal structure TAM1-Pks13 complex (PDB entry 5V3X). linear QSAR built, correlating computed gas phase enthalpies formation ( order to find active conformations TAMs. Furthermore, taking into account implicit solvent effect entropy changes upon ligand binding, superior brought forth, complexation Gibbs’ free energies . Using TAMs, built pharmacophore (PH4) which used virtually screen analogs included virtual combinatorial library (VCL) compounds containing scaffolds. The PH4 screened VCL, formerly filtered Lipinski’s rule-of-five, identify new analogs.
 Results: Gas model: , ; aqueous PH4-based screening retained 109 TAM analogues. Finally, profiles these analogues were compared current orally administered antituberculosis drugs, former found be almost 92 times more than TAM2 .
 Conclusion: This computational approach, combines molecular mechanics Poisson–Boltzmann (PB) solvation theory, model, analysis Pks13-TAMs interaction energies, VCL compounds, inference ADME properties resulted suggested inhibitors.