An in‐silico investigation of fluoride ions impact on pancreatic lipase

Abstract

Fluorine is a halogen beneficial to teeth and bones at a lower concentration. But in excess, it is a toxin and causes adverse effects. Fluoride is toxic to enzymes generally when it inhibits the enzyme activity involved in metabolic pathways. Here we study invitro and invivo findings on the interaction of fluoride on the enzymes Aconitase, Adenylyl cyclase, Arginase, Cytochrome‐c‐oxidase, Glucose‐6‐phosphatase, Protein phosphatase, Succinate dehydrogenase from liver and lipase from pancreas by using molecular docking and simulations to gain insights into the mechanism by which fluoride modifies the activity of pancreatic lipase. our molecular modeling and docking studies identified that lipase is the most strongly inhibited enzyme compared to other enzymes mentioned above with −0.42 Kcal/mol binding energy and 495.78 milli molar of predicted IC50 value with interaction with Phe227 residue. To further validate this, we have taken the lipase enzyme in presence of fluoride ions for molecular dynamic simulations of 100 ns. To analyze the impact of fluoride ions on the lipase dynamics, two different simulations of 100 ns each were performed. In one simulation, we have simulated lipase in its apo form in the aqueous environment without any fluoride ions and in another simulation lipase in its apo form was kept in the presence of randomly placed fluoride ions countered with sodium ions to maintain the pH as neutral. The simulation analysis revealed that major fluctuations in lipase was observed between 230 and 300 residues in presence of fluoride ions. Interestingly, this is the exact location of the “lid” like acting loop of residues responsible for the inward/outward movement of the substrate to lipase catalytically active site containing catalytic triad of residues Leu153, His263, and Pro177. His263 residue random flip is believed to be the critical incident that causes the substrate's inward/outward movement at the catalytically active site coordinated by “lid” opening, providing enough space for the substrate.