Utility of the Hard/Soft Acid−Base Principle via the Fukui Function in Biological Systems

Abstract

The hard/soft acid-base principle has long been known to be an excellent predictor of chemical reactivity. The Fukui function, a reactivity descriptor from conceptual density functional theory, has been shown to be related to the local softness of a system. The usefulness of the Fukui function is explored and demonstrated herein for three common biological problems: ligand docking, active site detection, and protein folding. In each type of study, a scoring function is developed based on the local HSAB principle using atomic Fukui indices. Even with necessary approximations for its use in large systems, the Fukui function remains a useful descriptor for predicting chemical reactivity and understanding chemical systems.

α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment

“…to study β‐lactam reactivity in the acylation step; ii . to determine the reactivity of protein/ligand systems; iii . to compare the reactivity of analogous sites across a series of related chemical species; and iv .…”

Docking of Covalent Ligands: Challenges and Approaches

“…Nevertheless, an approach to computationally scan a protein surface for sufficiently reactive residues and targeting them with covalent ligands could be of high interest. Studies such as those of Fukushima et al., in which semiempirical MO calculations on entire enzymes were used to predict their functional sites, or of Faver et al . for active site detection, may guide the way into such a direction.…”

Discovery of Novel Peptidomimetics as Irreversible CHIKV NsP2 Protease Inhibitors Using Quantum Mechanical‐Based Ligand Descriptors

“…Furthermore, extensive molecular modeling studies including covalent docking study, lowest unoccupied molecular orbital (LUMO) energies and the atomic condensed Fukui functions calculations were performed. These calculations had been previously reported in determining the reactivity in biological systems and studying the binding of wide range of covalent inhibitors , including cysteine protease inhibitors .…”

“…The ligand were subjected to a more robust geometry optimization at the B3LYP/6‐31G* level and a single‐point calculations at the B3LYP/6‐31 + G* level of theory to calculate the LUMO energies and extract the natural bond orbital (NBO) populations using the gaussian package . For cysteine1013, the active cysteine, we assumed a negatively charged species (cysteine anion) and the calculations were carried out at the same level of theory and basis set as the studied ligands.…”

“…where f + is the susceptibility of atom k to nucleophilic attack; f À is the susceptibility of atom k to electrophilic attack; P is the atomic electronic population; and N is the total number of electrons of the system. The ligand were subjected to a more robust geometry optimization at the B3LYP/6-31G* level and a single-point calculations at the B3LYP/6-31 + G* level of theory to calculate the LUMO energies and extract the natural bond orbital (NBO) populations using the GAUSSIAN package (27). For cysteine1013, the active cysteine, we assumed a negatively charged species (cysteine anion) and the calculations were carried out at the same level of theory and basis set as the studied ligands.…”