The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free-energy difference between pairs of ligands. Thus, the comparison of multiple ligands requires the construction of a “state graph”, in which the compounds are connected by alchemical transformations. The computational cost can be optimized by reducing the state graph to a minimal set of transformations. However, this may require individual adaptation of the sampling strategy if a transformation process does not converge in a given simulation time. In contrast, path-free methods like replica-exchange enveloping distribution sampling (RE-EDS) allow the sampling of multiple states within a single simulation without the pre-definition of alchemical transition paths. To optimize sampling and convergence, a set of RE-EDS parameters needs to be estimated in a pre-processing step. Here, we present an automated procedure for this step that determines all required parameters, improving the robustness and ease of use of the methodology. To illustrate the performance, the relative binding free energies are calculated for a series of checkpoint kinase 1 inhibitors containing challenging transformations in ring size, opening/closing, and extension, which reflect changes observed in scaffold hopping. The simulation of such transformations with RE-EDS can be conducted with conventional force fields and, in particular, without soft bond-stretching terms.

Biaryl molecules are one of the most ubiquitous pharmacophores found in natural products and pharmaceuticals. In spite of this, existing molecular mechanics force fields are unable to accurately reproduce their torsional energy profiles, except in a few well-parametrized cases. This effectively limits the ability of structure-based drug design methods to correctly identify hits involving biaryls with confidence (eg. during virtual screening, employing docking and/or molecular dynamics simulations). Continuing in our endeavor to quantify organic chemistry principles, we showed that the torsional energy profile of biaryl compounds could be computed on-the-fly based on the electron-richness/deficiency of the aromatic rings. This method, called H-TEQ 4.0, was developed using a set of 131 biaryls. It was subsequently validated on a separate set of 100 diverse biaryls, including multi-substituted, bicyclic and tricyclic drug-like molecules, and produced an average RMSE of 0.95 kcal•mol -1 . For comparison, GAFF2 produced an RMSE of 3.88 kcal•mol -1 , owing to problems associated with the transferability of torsion parameters. The success of H-TEQ 4.0 provided further evidence that force fields could transition to become atom type-independent, providing that the correct underlying chemical principles are used. Overall, this method solved the problem of transferability of biaryl torsion parameters, while simultaneously improving the overall accuracy of the force field.

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Free-energy differences between pairs of end-states can be estimated based on molecular dynamics (MD) simulations using standard pathway-dependent methods such as thermodynamic integration (TI), free-energy perturbation, or Bennett’s acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS), on the other hand, allows for the sampling of multiple end-states in a single simulation without the specification of any pathways. In this work, we use the RE-EDS method as implemented in GROMOS together with generalized AMBER force-field (GAFF) topologies, converted to a GROMOS-compatible format with a newly developed GROMOS++ program amber2gromos , to compute relative hydration free energies for a series of benzene derivatives. The results obtained with RE-EDS are compared to the experimental data as well as calculated values from the literature. In addition, the estimated free-energy differences in water and in vacuum are compared to values from TI calculations carried out with GROMACS. The hydration free energies obtained using RE-EDS for multiple molecules are found to be in good agreement with both the experimental data and the results calculated using other free-energy methods. While all considered free-energy methods delivered accurate results, the RE-EDS calculations required the least amount of total simulation time. This work serves as a validation for the use of GAFF topologies with the GROMOS simulation package and the RE-EDS approach. Furthermore, the performance of RE-EDS for a large set of 28 end-states is assessed with promising results.

Applications of computational methods to predict binding affinities for protein/drug complexes are routinely used in structure-based drug discovery. Applications of these methods often rely on empirical Force Fields and their associated parameter sets and atom types. However, it is widely accepted that FFs cannot accurately cover the entire chemical space of drug like molecules, due to the restrictive cost of parametrization and the poor transferability of existing parameters. To address these limitations, initiatives have been carried out to develop more transferable methods, in order to allow for more rigorous descriptions of all possible drug-like molecules. We have previously reported H-TEQ, a method which does not rely on atom types. This method incorporates well established chemical principles to assign parameters to organic molecules. The previous implementation of H-TEQ only covered saturated and lone pair containing molecules; here we report our efforts to incorporate conjugated systems into our model. The developed model (H-TEQ3.0) has been validated on a wide variety of molecules from aryls containing heteroatoms, alkyls, and fused ring systems. Our method performs on par with one of the most commonly used FFs (GAFF2), without relying on atom types or any prior parametrization. In fact, our method is applicable to virtually any conjugated organic molecule.