Computational biotechnology: Prediction of competitive substrate inhibition of enzymes by buffer compounds with protein–ligand docking

► Buffers can inhibit enzyme activity by binding competitively at the active site. ► The inhibitory potential of buffers can be predicted with chemoinformatic methods. ► We apply protein–ligand docking, typically used in drug-design, to this problem. ► Evaluation of the method on nine enzymes shows prediction of the correct trend. In vitro enzymatic activity highly depends on the reaction medium. One of the most important parameters is the buffer used to keep the pH stable. The buffering compound prevents a severe pH-change and therefore a possible denaturation of the enzyme. However buffer agents can also have negative effects on the enzymatic activity, such as competitive substrate inhibition. We assess this effect with a computational approach based on a protein–ligand docking method and the HYDE scoring function. Our method predicts competitive binding of the buffer compound to the active site of the enzyme. Using data from literature and new experimental data, the procedure is evaluated on nine different enzymatic reactions. The method predicts buffer–enzyme interactions and is able to score these interactions with the correct trend of enzymatic activities. Using the new method, possible buffers can be selected or discarded prior to laboratory experiments.