Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of "focusing" on one specific conformational state that binds to a protein. The calculated conformer focusing term made a considerable difference of 5-10 kJ/mol in computed relative binding free energies of studied Syk inhibitors and significantly improved the resulting accuracy of predictions.