Three-Dimensional Quantitative Structure−Activity Relationship Analysis of the New Potent Sulfonylureas Using Comparative Molecular Similarity Indices Analysis

Abstract

The present study describes the implementation of a new three-dimensional quantitative structure-activity relationship (3D-QSAR) technique: comparative molecular similarity indices analysis (CoMSIA) to a set of novel herbicidal sulfonylureas targeted acetolactate synthase. Field expressions in terms of similarity indices in CoMSIA were applied instead of the usually used Lennard-Jones and Coulomb-type potentials in CoMFA. Two different kinds of alignment techniques including field-fit alignment and atom-by-atom fits were used to produce the molecular aggregate. The results indicated that those two alignment rules generated comparative 3D-QSAR models with similar statistical significance. However, from the predictive ability of the test set, the models from the alignment after maximal steric and electrostatic optimization were slightly better than those from the simple atom-by-atom fits. Moreover, systematic variations of some parameters in CoMSIA were performed to search the best 3D-QSAR model. A significant cross-validated q 2 was obtained, indicating the predictive potential of the model for the untested compounds; meanwhile the predicted biological activities of the five compounds in the test set were in good agreement with the experimental values. The CoMSIA coefficient contour plots identified several key features explaining the wide range of activities, which were very valuable for us in tracing the properties that really matter and getting insight into the potential mechanisms of the intermolecular interactions between inhibitor and receptor, especially with respect to the design of new compounds.

Structure-activity relationships for a new family of sulfonylurea herbicides

“…Previously published 3D-QSAR analyses of sulfonylurea herbicides [19][20][21][22][23][24][25][26] suffer from several shortcomings. Firstly, the assumed bioactive conformation was based on either the structures of sulfonylureas crystallized as free molecules [20][21][22][23]25] or their low energy conformers calculated theoretically [19,24,26].…”

“…Firstly, the assumed bioactive conformation was based on either the structures of sulfonylureas crystallized as free molecules [20][21][22][23]25] or their low energy conformers calculated theoretically [19,24,26]. However, it is now known that none of these conformations match that observed when a sulfonylurea is bound to its target enzyme [7,8].…”

“…However, it is now known that none of these conformations match that observed when a sulfonylurea is bound to its target enzyme [7,8]. Secondly, most activity data employed in previous QSAR investigations were obtained using in vivo experiments [19][20][21][22][23][24][25][26]. Herbicidal activity depends ultimately upon inhibition of AHAS, but there are differences between in vivo and in vitro effects of these compounds due to barriers between the site of application and the intracellular target, degradation and detoxification by the plant, and so on.…”

3D-QSAR and molecular docking studies of hydroxamic acids as peptide deformylase inhibitors

“…The rest molecules were built based on molecule 15 by changing the required substituent and minimized similarly. Molecular alignment is the most important input variable in CoMFA and CoMSIA studies (Sippl, 2000;Zhu et al, 2001;Hou et al, 2000). All molecules were aligned based on the assumption that they bind to PDF in the same manner.…”

“…The CoMSIA models were generated based on the same lattice box used for the CoMFA calculations (Klebe et al, 1994). The five similarity indices in CoMSIA, that is, steric, electrostatic, hydrophobic, H-bond donor, and H-bond acceptor descriptors, were calculated using the standard settings (probe with charge ?1, radius of 1 Å and hydrophobicity of ?1, hydrogen bond donating of ?1, hydrogen bond acceptor of ?1, attenuation factor of 0.3 for Gaussian distance-dependent function, and grid spacing of (Hou et al, 2000(Hou et al, , 2002Hou and Xu, 2001;Klebe and Abraham, 1999).…”