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This is particularly true for one of the key parameters to be optimized during ligand development, the free energy of binding (<jats:inline-formula><jats:alternatives><jats:tex-math>$$\\Delta$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mi>\u0394<\/mml:mi>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula>G<jats:inline-formula><jats:alternatives><jats:tex-math>$$_{\\text {bind}}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:msub>\n                    <mml:mrow\/>\n                    <mml:mtext>bind<\/mml:mtext>\n                  <\/mml:msub>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula>). Here, we developed simple models based on the Linear Interaction Energy approximation to free energy calculation for a G protein-coupled receptor, the serotonin receptor 2A, and critically evaluated their accuracy. 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