TY - JOUR
T1 - A Comparative Linear Interaction Energy and MM/PBSA Study on SIRT1-Ligand Binding Free Energy Calculation
AU - Rifai, Eko Aditya
AU - van Dijk, Marc
AU - Vermeulen, Nico P.E.
AU - Yanuar, Arry
AU - Geerke, Daan P.
N1 - Funding Information:
Dr. Berin Karaman (Biruni University) and Prof. Wolfgang Sippl (Martin-Luther-University of Halle-Wittenberg) are gratefully acknowledged for sharing their SIRT1–ligand complex structures with us. We thank The Netherlands Organisation for Scientific Research (NWO, VIDI Grant 723.012.105) for financial support, and E.A.R. gratefully acknowledges financial support from the Indonesia Endowment Fund for Education (LPDP), Ministry of Finance, Republic of Indonesia.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/9/23
Y1 - 2019/9/23
N2 - Binding free energy (ΔGbind) computation can play an important role in prioritizing compounds to be evaluated experimentally on their affinity for target proteins, yet fast and accurate ΔGbind calculation remains an elusive task. In this study, we compare the performance of two popular end-point methods, i.e., linear interaction energy (LIE) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), with respect to their ability to correlate calculated binding affinities of 27 thieno[3,2-d]pyrimidine-6-carboxamide-derived sirtuin 1 (SIRT1) inhibitors with experimental data. Compared with the standard single-trajectory setup of MM/PBSA, our study elucidates that LIE allows to obtain direct ("absolute") values for SIRT1 binding free energies with lower compute requirements, while the accuracy in calculating relative values for ΔGbind is comparable (Pearson's r = 0.72 and 0.64 for LIE and MM/PBSA, respectively). We also investigate the potential of combining multiple docking poses in iterative LIE models and find that Boltzmann-like weighting of outcomes of simulations starting from different poses can retrieve appropriate binding orientations. In addition, we find that in this particular case study the LIE and MM/PBSA models can be optimized by neglecting the contributions from electrostatic and polar interactions to the ΔGbind calculations.
AB - Binding free energy (ΔGbind) computation can play an important role in prioritizing compounds to be evaluated experimentally on their affinity for target proteins, yet fast and accurate ΔGbind calculation remains an elusive task. In this study, we compare the performance of two popular end-point methods, i.e., linear interaction energy (LIE) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), with respect to their ability to correlate calculated binding affinities of 27 thieno[3,2-d]pyrimidine-6-carboxamide-derived sirtuin 1 (SIRT1) inhibitors with experimental data. Compared with the standard single-trajectory setup of MM/PBSA, our study elucidates that LIE allows to obtain direct ("absolute") values for SIRT1 binding free energies with lower compute requirements, while the accuracy in calculating relative values for ΔGbind is comparable (Pearson's r = 0.72 and 0.64 for LIE and MM/PBSA, respectively). We also investigate the potential of combining multiple docking poses in iterative LIE models and find that Boltzmann-like weighting of outcomes of simulations starting from different poses can retrieve appropriate binding orientations. In addition, we find that in this particular case study the LIE and MM/PBSA models can be optimized by neglecting the contributions from electrostatic and polar interactions to the ΔGbind calculations.
UR - http://www.scopus.com/inward/record.url?scp=85072587248&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.9b00609
DO - 10.1021/acs.jcim.9b00609
M3 - Article
C2 - 31461271
AN - SCOPUS:85072587248
VL - 59
SP - 4018
EP - 4033
JO - Journal of Chemical Documentation
JF - Journal of Chemical Documentation
SN - 1549-9596
IS - 9
ER -