The Structure and Quantum-Mechanical Framework for a Series of Hydroxamic Acid Derivatives as Strong Inhibitors Against Anthrax Lethal Factor

Quantum chemical techniques such as density functional theory (DFT) have become a powerful tool in the investigation of the molecular structure and have growing applications in biological systems [1-4]. In this work, a number of 14 compounds of hydroxamic acid (HydA) derivatives, with the activity in the range of sub-nanomolar versus anthrax lethal factor, were used to study their quantum mechanical and physico-chemical properties. The geometry of free compounds (HydA) and in complex with were separately optimized and minimized by DFT/M062X method. Different basis sets including 6-31G(d,p) and 6- 311++G(d,p) were conducted for structure optimization and minimization, respectively. The optimized free compounds of HydA were applied as initial conformations to generate complexes and follow the additional optimization process. Stability of the molecules arising from hyper-conjugative interactions, and charge delocalization has been analyzed using natural bond orbital analysis (NBO). The first order hyperpolarizability and molecular electrostatic potential (MEP) were also performed to predict the reactive sites for electrophilic and nucleophilic attack. Moreover, the HOMO and LUMO energies were analyzed and show that charge transfer occurs within the molecule. Data clearly indicated that the strong activities of the series of hydroxamic acid derivatives against anthrax lethal factor are mainly because of their chelating properties and conformational flexibility of the structures with freely changing by forming complexes of .