Quantitative structure property relationship (QSPR) studies for predicting renal clearance of cephalosporins

Abstract

ß-lactam antibiotics are of clinical importance for treatment of bacterial infections. Several penicillins and cephalosporins with broad spectra of activity and high stability against various β-lactamases have been developed and introduced in clinical practice. Due to increasing prevalence of antibiotic resistance, efforts to synthesize more compounds for better activity are still on. Traditionally, a combination of serendipity and empiricism has been the basis of new drug discovery.  Trial and error synthesis of compounds and their random screening for activity have proved to be both time-consuming and uneconomical. Hence, predicting pharmacokinetic parameters, of a new molecule, in an early stage of drug design, is of as high importance as the activity of the compound. With rapid advances in computation power of machines and availability of experimental data, these ADME properties can now be better predicted by using suitable computational methods. In the present study, a quantitative structure-property relationship study of 32 cephalosporins to renal clearance was performed with descriptors of molecular structures. Good correlations of Renal Clearance were obtained with constitutional and electrostatic descriptors like Bond length between C-O, bond length between H-O bonds, maximum bond length between H-N bond, number of H-O bonds and charge of all C atoms. High values of R² (0.8397) and Q² (0.7746) were indicative of high predictive power of this correlation. Also, lower R² RAND value compared to R² indicates that the correlations obtained are not chance correlations and hence can be used for prediction purposes.