Exploring Chloride Selectivity and Halogenase Regioselectivity of the SalL Enzyme through Quantum Mechanical/Molecular Mechanical Modeling.

The catalytic mechanism of SalL chlorinase has been investigated by combining quantum mechanical/molecular mechanical (QM/MM) techniques and umbrella sampling simulations to compute free energy profiles. Our results shed light on the interesting fact that the substitution of chloride with fluorine in SalL chlorinase leads to a loss of halogenase activity. The potential of mean force based on DFTB3/MM analysis shows that fluorination corresponds to a barrier 13.5 kcal·mol-1 higher than chlorination. Additionally, our results present a molecular description of SalL acting as a chlorinase instead of a methyl-halide transferase.

Targeting shikimate pathway: In silico analysis of phosphoenolpyruvate derivatives as inhibitors of EPSP synthase and DAHP synthase.

The shikimate pathway consists of seven enzymatic steps involved in the conversion of erythrose-4-phosphate and phosphoenolpyruvate to chorismate and also responsible to the production of aromatic amino acids, such as phenylalanine, tyrosine, and tryptophan which are essential to the bacterial metabolism. The 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS) and 5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) catalyze important steps in the shikimate pathway using as substrate the phosphoenolpyruvate (PEP). Due to the importance of PEP in shikimate pathway, its structure has been investigated to develop new bioinspired competitive inhibitors against DAHPS and EPSPS. In the present study, we perform a literature survey of 28 PEP derivatives, then we analyzed the selectivity and affinity of these compounds against the EPSPS and DAHPS structures using consensual molecular docking, pharmacophore prediction, molecular dynamics (MD) simulations, and binding free energy calculations. Here, we propose consistent binding modes of the selected ligands and indicate that their structures show interesting pharmacophoric properties related to multi-targets inhibitors for both enzymes. Our computational results are supported by previous experimental findings related to the interactions of PEP derivatives with DAHPS and EPSPS structures.