Dissecting errors in ligand structure by determining conformational changes due to the protein environment
Ligand conformational strain energy(LCSE)is an important parameter in computer-aided drug discovery.LCSE may be calculated through quantum mechanical(QM)computations by comparing free and protein pocket-bound ligand structures.How-ever,there is still a dispute on the plausible LCSE range and the methodology to obtain it.In this work,8 highly flexible ligand structures with a good variety of patterns were chosen to be optimized step-by-step with energy calculations to analyze the differences in struc-ture and relative energies from protein-bound ligands to free ligand with the minimum local energy.The structures with resolutions between high(0.86 × 10-10)and medium(3.1 × 10-10)are calculated through 3 QM methods,namely the density functional theory(DFT)with the M062X-D3 function as well as Hartree-Fock and GFN1-xTB approaches.QM calculation results show that LCSE was lower than 6.0 kcal/mol.In several cases,the energy differences between bound and unbound ligand structures was mainly due to signif-icant errors in the geometrical parameters of the former,highlighting the need of accurate experimental determination of protein-bound ligand structures prior to LCSE analyses.
protein-ligand complexesstrain energypotential energy surfacedensity functional theory(DFT)Hartree-FockGFN1-xTB
NETL
NSTL
万方数据
