Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?

被引：37
作者：
Liu, Shuai [1 ,2 ]
Wang, Lingle [3 ]
Mobley, David L. [1 ,2 ]
机构：
[1] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA
[3] Schrodinger Inc, New York, NY 10036 USA
来源：
JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2015年 / 55卷 / 04期
基金：
美国国家卫生研究院;
关键词：
GENERATION; EFFICIENT; MODEL;
D O I：
10.1021/acs.jcim.5b00057
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Our interest is relative binding free energy (RBFE) Calculations based on molecular k simulations. These are promising tools for lead optimization in drug discovery, computing changes in binding free energy due to modifications of a lead compound. However, in the "alchemical' framework for RUE calculations, sorbe types of mutations have the potential to introduce error into the computed binding free energies. Here we explore the magninide of this error in several different model binding calculations. We find that some of the calculations involving ring breaking have significant errors, and these errors are especially large in bridged ring systems. Since the error is a function of ligand strain, which is impredictablein advance, we believe that ring breaking should be avoided when possible.
引用
收藏
页码：727 / 735
页数：9
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  • [11] COMPARISON OF SIMPLE POTENTIAL FUNCTIONS FOR SIMULATING LIQUID WATER
    JORGENSEN, WL
    CHANDRASEKHAR, J
    MADURA, JD
    IMPEY, RW
    KLEIN, ML
    [J]. JOURNAL OF CHEMICAL PHYSICS, 1983, 79 (02) : 926 - 935
  • [12] Predicting hydration free energies using all-atom molecular dynamics simulations and multiple starting conformations
    Klimovich, Pavel V.
    Mobley, David L.
    [J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2010, 24 (04) : 307 - 316
  • [13] Lead optimization mapper: automating free energy calculations for lead optimization
    Liu, Shuai
    Wu, Yujie
    Lin, Teng
    Abel, Robert
    Redmann, Jonathan P.
    Summa, Christopher M.
    Jaber, Vivian R.
    Lim, Nathan M.
    Mobley, David L.
    [J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2013, 27 (09) : 755 - 770
  • [14] Hit Identification and Binding Mode Predictions by Rigorous Free Energy Simulations
    Michel, Julien
    Essex, Jonathan W.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (21) : 6654 - 6664
  • [15] Protein-ligand complexes: Computation of the relative free energy of different scaffolds and binding modes
    Michel, Julien
    Verdon, Marcel L.
    Essex, Jonathan W.
    [J]. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 2007, 3 (05) : 1645 - 1655
  • [16] Rigorous Free Energy Calculations in Structure-Based Drug Design
    Michel, Julien
    Foloppe, Nicolas
    Essex, Jonathan W.
    [J]. MOLECULAR INFORMATICS, 2010, 29 (8-9) : 570 - 578
  • [17] Perspective: Alchemical free energy calculations for drug discovery
    Mobley, David L.
    Klimovich, Pavel V.
    [J]. JOURNAL OF CHEMICAL PHYSICS, 2012, 137 (23)
  • [18] Alchemical prediction of hydration free energies for SAMPL
    Mobley, David L.
    Liu, Shaui
    Cerutti, David S.
    Swope, William C.
    Rice, Julia E.
    [J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2012, 26 (05) : 551 - 562
  • [19] A COMPARISON OF ALTERNATIVE APPROACHES TO FREE-ENERGY CALCULATIONS
    PEARLMAN, DA
    [J]. JOURNAL OF PHYSICAL CHEMISTRY, 1994, 98 (05) : 1487 - 1493
  • [20] Separated topologies-A method for relative binding free energy calculations using orientational restraints
    Rocklin, Gabriel J.
    Mobley, David L.
    Dill, Ken A.
    [J]. JOURNAL OF CHEMICAL PHYSICS, 2013, 138 (08)
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