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In this study, we compare the performance of two popular end-point methods, i.e., linear interaction energy (LIE) and molecular mechanics\/Poisson\u2013Boltzmann surface area (MM\/PBSA), with respect to their ability to correlate calculated binding affinities of 27 thieno\u00ad[3,2-d]\u00adpyrimidine-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 (\u201cabsolute\u201d) values for SIRT1 binding free energies with lower compute requirements, while the accuracy in calculating relative values for \u0394Gbind is comparable (Pearson\u2019s 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 \u0394Gbind calculations.<\/jats:p>","DOI":"10.1021\/acs.jcim.9b00609","type":"journal-article","created":{"date-parts":[[2019,8,28]],"date-time":"2019-08-28T15:25:50Z","timestamp":1567005950000},"page":"4018-4033","source":"Crossref","is-referenced-by-count":91,"title":["A Comparative Linear Interaction Energy and MM\/PBSA\nStudy on SIRT1\u2013Ligand Binding Free Energy Calculation"],"prefix":"10.1021","volume":"59","author":[{"given":"Eko Aditya","family":"Rifai","sequence":"first","affiliation":[{"name":"Vrije Universiteit Amsterdam , , De Boelelaan 1108 , ,","place":["Amsterdam, The Netherlands, 1081 HZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Vrije Universiteit Amsterdam , , De Boelelaan 1108 , ,","place":["Amsterdam, The Netherlands, 1081 HZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico P. 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