LEADOPT: an automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors

European Journal of Medicinal Chemistry
Guo-Bo LiSheng-Yong Yang

Abstract

Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib...Continue Reading

References

Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·I D KuntzP A Kollman
May 31, 2003·Nature Reviews. Drug Discovery·Terry Kenakin
Apr 6, 2005·Drug Discovery Today·Cele Abad-Zapatero, James T Metz
Sep 28, 2005·Expert Opinion on Therapeutic Targets·Marina UlanovaA Dean Befus
Dec 16, 2005·Nature·Napoleone Ferrara, Robert S Kerbel
Oct 4, 2006·Nature Reviews. Drug Discovery·Scott WilhelmSusan Kelley
Oct 16, 2007·Current Opinion in Chemical Biology·Campbell McInnes
Jan 29, 2008·Journal of Combinatorial Chemistry·J Phillip KennedyCraig W Lindsley
Apr 3, 2008·Journal of Medicinal Chemistry·Charles H ReynoldsScott D Bembenek
May 6, 2008·Journal of Pharmaceutical and Biomedical Analysis·Chang-Ying MaYu-Quan Wei
Oct 23, 2008·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Hui ZhangSheng-Yong Yang
Feb 28, 2009·Nature Reviews. Drug Discovery·György M Keserü, Gergely M Makara
Mar 26, 2009·Accounts of Chemical Research·William L Jorgensen
May 5, 2009·European Journal of Medicinal Chemistry·Aggeliki PolitiThomas Mavromoustakos
Sep 25, 2009·Current Opinion in Pharmacology·Lorenz M Mayr, Dejan Bojanic
Sep 30, 2009·Journal of Chemical Information and Modeling·Orazio NicolottiAngelo Carotti
May 15, 2010·Nature Reviews. Immunology·Attila MócsaiVictor L J Tybulewicz
Oct 1, 2010·The New England Journal of Medicine·Michael E WeinblattDaniel B Magilavy
Jun 1, 2009·Nature Chemistry·Christopher W Murray, David C Rees
Sep 29, 2011·Nucleic Acids Research·Anna GaultonJohn P Overington
Aug 1, 1988·Journal of the American Chemical Society·R D CramerJ D Bunce
Sep 19, 2012·Proceedings of the National Academy of Sciences of the United States of America·Michele McTigueRobert S Kania
Jan 29, 2013·Journal of Medicinal Chemistry·Fernando PadillaMatthew C Lucas
Feb 12, 2013·Journal of Chemical Information and Modeling·Guo-Bo LiSheng-Yong Yang
Apr 1, 2007·Expert Opinion on Drug Discovery·Cele Abad-Zapatero
Feb 15, 2014·Cancer Cell·Alexandre PuissantKimberly Stegmaier

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Citations

Apr 30, 2017·Chemical Science·Guo-Bo LiChristopher J Schofield
Jul 1, 2017·Journal of Chemical Information and Modeling·Guo-Bo LiSheng-Yong Yang
Apr 13, 2018·Future Medicinal Chemistry·Ziyan ZhouXiaoming Zha
Aug 2, 2017·Chemical Biology & Drug Design·Sha LiuYong Wu
Feb 8, 2018·Organic & Biomolecular Chemistry·Shu ZhouJin-Ku Bao
Nov 30, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xing WangXia Wu
Nov 20, 2016·Science China. Life Sciences·Lingling YangXianggui Chen

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