caa a22 4500 445878983 CHVBK 20180317145536.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11030-010-9243-8 doi (NATIONALLICENCE)springer-10.1007/s11030-010-9243-8 Predictive models for nucleoside bisubstrate analogs as inhibitors of siderophore biosynthesis in Mycobacterium tuberculosis [Elektronische Daten] pharmacophore mapping and chemometric QSAR study [Nilesh Tawari, Mariam Degani] Inhibitors of aryl acid adenylating enzymes (AAAE), known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. In this article, we report the development of a robust pharmacophore model and investigation of structure-activity relationship of several nucleoside bisubstrate analogs reported as MbtA inhibitors. The developed pharmacophore model revealed the importance of two hydrogen bond donors and one hydrogen bond acceptor features. Furthermore, it was found that an aromatic ring at the distal part of molecule away from the two aromatic rings of adenyl moiety is a critical requirement for the tight binding of inhibitor. The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for training set (r 2 = 0.97, SD =0.23, F =310.6, N = 48) and test set (Q 2=0.71, RMSE = 0.65, Pearson-R=0.85, N = 15). Structure-activity relationship investigation further revealed that bulky substitutions at the C-6 position of adenyl moiety is detrimental to activity, while hydrophobic substitutions can be tolerated at C-2 position. Taken together, the PLS-generated QSAR regression cubes along with developed pharmacophore model provide a qualitative picture of the active site and can be used as a powerful tool for the rational modification of bisubstrate inhibitors of MbtA in search of better antitubercular agents. Furthermore, a three-class classification chemometric QSAR model was developed using molecular descriptors for the prediction of whole-cell activity which could be used in the predictive layer for screening of compounds before synthesis. Springer Science+Business Media B.V., 2010 Siderophore nationallicence Tuberculosis nationallicence Pharmacophore mapping nationallicence 3D-QSAR nationallicence Tawari Nilesh Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), 400019, Mumbai, India aut Degani Mariam Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), 400019, Mumbai, India aut Molecular Diversity Springer Netherlands 15/2(2011-05-01), 435-444 1381-1991 15:2<435 2011 15 11030 https://doi.org/10.1007/s11030-010-9243-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11030-010-9243-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tawari Nilesh Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), 400019, Mumbai, India aut NATIONALLICENCE 700 1- Degani Mariam Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), 400019, Mumbai, India aut NATIONALLICENCE 773 0- Molecular Diversity Springer Netherlands 15/2(2011-05-01), 435-444 1381-1991 15:2<435 2011 15 11030 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer