Probing the Structure-Property Relationship of Functionalized Cephalexin Derivatives: A Computational Analysis of Nonlinear Optical Properties and Molecular Docking with MMP-2

Abstract

Cephalexin is a widely used β-lactum antibiotic, the molecular structure of which is amenable to a great deal of chemical modification, allowing manipulation of its physicochemical properties. This research aims to ascertain the effect of specific chemical modification of Cephalexin on its potential for uses other than antibacterial in the area of NLO and enzyme inhibition. The purpose of the research is to systematically study, in a coordinated in silico investigation, the properties of different substituents (fluoro, methoxy, nitro, chloro, hydroxy-methyl, and cyano) on the electronic structure, NLO response, and biological binding character of Cephalexin. The work makes use of DFT calculations incorporating a B3LYP functional with a complete 6-311++G(d,p) basis for the optimization of geometries and calculation of electronic and NLO properties. Molecular docking simulations will also be performed using Auto Dock Vina to allow assessment of the binding affinities and means of interaction of the derivatives at the active site of the Matrix Metalloproteinase-2 (MMP-2, PBD ID: 1J7M). The introduction of strong e.e. withdrawing groups gives rise to an enormous increase in NLO response. The nitro-substituted derivative (M3) showed the highest value of first hyperpolarizability 15.82 x 10⁻³⁰ esu for β₀, which is a figure more than 35 times greater than that of the parent cephalexin and a considerable enhancement of NLO character. On the other hand, the hydroxy-methyl derivative (M5) gave the highest binding affinity of -7.2 Kcal/mol with MMP-2, which is believed to be attributable to the gain of an additional hydrogen bond with the important active site residue GLU27 This work establishes, therefore, a clear structure-property relationship for substituted functionalized Cephalexin. The results show that nitro functionalization is a capable vehicle for extensive chemical modification.