Computational (MP2 and DFT) modeling of the substrate/inhibitor interaction with the LDH active pocket in the gas phase and aqueous solution: bimolecular charged (pyruvate/oxamate–guanidinium cation) and neutral adducts (pyruvic/oxamic acids–guanidine)

Two types of bimolecular adducts were studied for the substrate and inhibitor of lactate dehydrogenase (LDH), one type of adducts between ionic species, α‐keto‐carboxylates (pyruvate and oxamate) and the guanidinium cation, and the other type of adducts between neutral species, α‐ketocarboxylic (pyruvic and oxamic) acids and guanidine. Calculations were performed in the gas phase and aqueous solution using the MP2 and PCM methods and the 6‐31++G** basis set. Application of the DFT(B3LYP) and PCM methods led to similar results. A change of the adducts' preference was observed when proceeding from the gas phase to aqueous solution. This change is in good agreement with the acidity–basicity scales in both phases. Formation constant (K_HB) for adduct between neutral species is greater for pyruvic than for oxamic acid in the gas phase, whereas a reverse situation takes place in aqueous solution, where the K_HB value for adduct between ionic species is smaller for pyruvate than for oxamate. The water molecules favor interactions of more polar oxamate with the guanidinium cation. Stronger interaction with this cation, a model of the arginine fragment of the LDH pocket, suggests that oxamate (inhibitor of LDH) has stronger binding properties in aqueous solution than pyruvate (substrate of LDH). Copyright © 2008 John Wiley & Sons, Ltd.