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 apowerful tool in the investigation of the molecular structure and have growing applications inbiological 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, wereused to study their quantum mechanical and physico-chemical properties. The geometry of freecompounds (HydA) and in complex with Zn2+ (HydA-Zn2+) were separately optimized andminimized 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. Theoptimized free compounds of HydA were applied as initial conformations to generate complexesHydA-Zn2+ and follow the additional optimization process. Stability of the molecules arisingfrom hyper-conjugative interactions, and charge delocalization has been analyzed using naturalbond orbital analysis (NBO). The first order hyperpolarizability and molecular electrostaticpotential (MEP) were also performed to predict the reactive sites for electrophilic andnucleophilic attack. Moreover, the HOMO and LUMO energies were analyzed and show thatcharge transfer occurs within the molecule. Data clearly indicated that the strong activities of theseries of hydroxamic acid derivatives against anthrax lethal factor are mainly because of theirchelating properties and conformational flexibility of the structures with freely changing byforming complexes of HydA-Zn2+.

کلیدواژه ها:

DFT ، NBO ، MEP ، Lethal Factor