Input structures for the complexes between p38α MAP kinase and the 18 inhibitors were prepared starting from the crystal structure (PDB: 1OUY 33 ) as described in the Supporting Information using the MCPRO 3.2 31 and BOMB 37 software packages. Ligand force fields were parametrized using the QUBEKit software package. Quantum chemistry geometry optimizations and frequency calculations were performed in Gaussian09 38 using the ωB97XD functional and 6-311++G(d,p) basis set. Equilibrium bond lengths and angles were extracted from the QM optimized geometry, and the bond-stretching and angle-bending force constants were derived from the QM Hessian matrix via the modified Seminario method with a vibrational scaling factor of 0.957. Constrained one-dimensional torsional optimizations were also performed using Gaussian09, with the same level of theory and basis set, in 15 • increments from 0 • to 360 • . Torsion parameter optimizations of dihedrals φ 1 and φ 2 were performed for each ligand separately using QUBEKit with no Boltzmann weighting or regularization. OPLS atom types were retained during torsion fitting to reduce the parameter search space, while all remaining small molecule torsion parameters were taken from the OPLS force field. Non-bonded parameter assignment was performed for both small molecules and the protein (2961 atoms) using the ONETEP linear-scaling density functional theory code and DDEC AIM analysis (Supporting Information). All bonded parameters of the protein were assigned from a transferable library that has been specifically designed to be compatible with the QUBE FF. Water molecules were described using the TIP4P water model. FEP/REST calculations were performed using the MCPRO software, version 3.2, which includes recent improvements to the efficiency of protein MC moves. Protocols were similar to those used previously and are described in the Supporting Information.