Interaction energy profile for diphenyl diselenide in complex with δ-aminolevulinic acid dehydratase enzyme using quantum calculations and a molecular fragmentation method

Abstract Studies has pointed out the selenocompound diphenyl diselenide [(PhSe) 2 ] as a novel promising drug with antioxidant, neuroprotective, anti-atherosclerotic and anti-inflammatory effects. In the opposite way, (PhSe) 2 can also present cytotoxic properties and inhibit the activity of δ-aminolevulinic acid dehydratase (δALAD) and other thiol-containing proteins. δALAD inhibition can impair heme biosynthesis and, consequently, affect the aerobic metabolism. In order to deepen the analysis of the molecular mechanisms concerning δALAD inhibition by (PhSe) 2 , we performed theoretical quantum calculations within the Density Functional Theory (DFT) approach related to the interaction energies between amino acid residues and (PhSe) 2 via Molecular Fragmentation with Conjugated Caps (MFCC) method. The quantum calculations revealed that interactions between (PhSe) 2 moieties and δALAD could occur up to 9 A distance from the (PhSe) 2 active site centroid located inside the TIM barrel active site of δALAD. In addition, Phe208, Phe79, Cys122, Cys124, Pro125, Asp120, Lys199, Lys252, and Cys132 presented stronger attractive interaction energies to (PhSe) 2 than to other closer residues and could be pointed out as essential for complex stability (interaction energy values ranging from −23.75 kcal·mol −1 to −11.74 kcal·mol −1 for DFT LDA/PWC and from −19.75 kcal·mol −1 to −6.76 kcal·mol −1 for DFT GGA/PW91). The analysis of the calculated energy values and the electrostatic potential together clarify that the two phenyl moieties in (PhSe) 2 are key players in strongly attracting to aromatic, hydrophobic, and positively charged side chains from residues of the δALAD active site. Consequently, the spatial orientation assumed by (PhSe) 2 allows the electrophile moiety Se-Se closer to thiolate groups of catalytic Cys122, Cys124, and Cys132, leading to consequent thiol oxidation and zinc release. In conclusion, these pieces of information may improve the previous understanding of the molecular docking model and could be useful to guide future studies concerning the rational design of novel diselenide-derived drugs with low affinity for δALAD.