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标题：Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA)
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作者：Vigneshwaran Namasivayam ; Katja Silbermann ; Jens Pahnke 等
期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2021
卷号：19
页码：3269-3283
DOI：10.1016/j.csbj.2021.05.018
出版社：Computational and Structural Biotechnology Journal
摘要：Computer-aided pattern analysis ( [email protected] ) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating [email protected] to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve [email protected] ’s prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original.
关键词：Well-studied ABC transporters ; ABCB1 (P-gp) ; ABCC1 (MRP1) ; ABCG2 (BCRP) ; Under-studied ABC transporters ( e.g;; ABCA7) ; Triple ;multitarget ;broad-spectrum ;promiscuous inhibitor ;antagonist ; Pan-ABC inhibition ;antagonism ;blockage (PANABC) ; Pattern analysis ( [email protected] ) ; Multitarget fingerprints ; Alzheimer's disease (AD) ; Multidrug resistance (MDR)