Exploration of physicochemical properties and molecular modeling studies of furanylamide analogs as antituberculosis agents

Abstract

In the present study, an attempt has been made to explore physicochemical requirements of furanylamide analogs for binding with Mycobacterium tuberculosis UDP-galactopyranose mutase. Sequential Multiple Linear Regression (SEQ-MLR) technique was used for the development of a quantitative structure-activity relationship. The quality of QSAR models obtained from SEQ-MLR is in acceptable statistical range (explained variance ranging from 77.0 to 91.3%). The statistical qualities of the SEQ-MLR equations were judged by the parameters like explained variance (r2adj), correlation coefficient (r), Standard Error of Estimate (SEE), and variance ratio (F) at specified Degrees of Freedom (df). The generated equations were internally validated using the leave-one-out technique. The selected equations were further validated using a test set considering a predictive squared correlation coefficient (r2pred). The study suggested the indispensable nature of the nitro group on furanylamide scaffold and decisiveness of the van der Waals volume for the activity. The toxicity of the furanylamide analogs might be reduced by limiting the number of hydrogen acceptor groups. The selectivity of the compounds was supported by 3D-Molecular Representation of Structure based on Electron Diffraction (3D-MoRSE) code at 24th signal by atomic weight and the presence of nitro group. The binding of furanylamide analogs in M. tuberculosis UDP-galactopyranose mutase enzyme was explored with the help of docking. The most stable ligand - enzyme complex of compound 2 showed that a ligand binds in the vicinity of the FAD. The nitro group buried in the positive charged pocket, which comprised of Arg-261 and Lys-164. depicted the crucial ionic interaction. The phenyl ring of the ligand plays a key role in the hydrophobic interaction by π-π stacking with Tyr-366 and Tyr-328. © 2007 WILEY-VCH Verlag GmbH & Co. KGaA.