Scaffold Hopping Transformations Using Auxiliary Restraints for Calculating Accurate Relative Binding Free Energies

Abstract

In silico screening of drug target interactions is a key part of the drug discovery process.Changes in the drug scaffold via contraction or expansion of rings, the breaking of rings and the introduction of cyclic structures from acyclic structures are commonly applied by medicinal chemists to improve binding affinity and enhance favorable properties of candidate compounds. These processes, commonly referred to as scaffold hopping, are challenging to model computationally. Although relative binding free energy (RBFE) calculations have shown success in predicting binding affinity changes caused by perturbing R-groups attached to a common scaffold, applications of RBFE calculations to modeling scaffold hopping are relatively limited. Scaffold hopping inevitably involves breaking and forming bond interactions of quadratic functional forms, which is highly challenging. A novel method for handling ring opening/closure/contraction/expansion and linker contraction/expansion is presented here. To the best of our knowledge, RBFE calculations on linker contraction/expansion have not been previously reported. The method uses auxiliary restraints to hold the atoms at the ends of a bond in place during the breaking and forming of the bonds. The broad applicability of the method was demonstrated by examining perturbations involving small molecule macrocycles and mutations of proline in proteins. High accuracy was obtained using the method for most of the perturbations studied. Unlike other methods that rely on λ-dependent functional forms for bond interactions, the method presented here can be employed using modern MD software without modification of codes or force field functions.

Relative Binding Free Energy between Chemically Distant Compounds Using a Bidirectional Nonequilibrium Approach

“…In the most straightforward ST implementation, the two compounds share a common topological structure with the same number of atoms, and a single atom is transformed to another (e.g., H into a halogen atom). When the number of atoms differs as in a so-called “R-group perturbation” 24 , 25 (e.g., H into CH 3 or CH into N in an aromatic cycle), “dummy” atoms are added to the common core structure. While these atoms are fully interacting on one end-state, at the other end, they are bound to the molecule with zero nonbonded parameters, except for 14 nonbonded interactions involving the dummy atoms.…”

“… 29 Recently, many ST schemes have been proposed for RBFE calculations to tackle scaffold hopping. 25 , 30 However, the approaches are involved, highly system-dependent, and, as such, not easily amenable to be implemented in automated high-throughput virtual screening for pharmaceutical applications. It should be finally said that the accuracy of ST RBFE calculations has been demonstrated to be dependent on the input poses to construct the perturbation map in congeneric series if sampling is incomplete, 15 a fact that may further limit the utility of ST RBFE in industrial projects.…”

Relative Binding Free Energy Calculations for Ligands with Diverse Scaffolds with the Alchemical Transfer Method

“…Wang et al introduced a customized soft bond stretch potential to smoothly form and break bonds. More recently, Zou et al introduced a scheme based on auxiliary restraining potentials to achieve the same goal. Multisite λ-dynamics has been presented as an alternative to scaffold hopping transformations involving ring opening and ring expansion/reduction .…”

“…introduced a customized soft-bond stretch potential to address the numerical instabilities encountered when forming and breaking covalent bonds in a single-topology context. More recently, Zou et al presented a method that uses a series of restraining potentials to address the same problem.…”

A Guide to In Silico Drug Design

“…Tang et al utilised FEP to guide the discovery of novel D-amino acids oxidase inhibitors, with good consistency shown between bioassay results and the energy calculations [ 369 ]. Zou et al developed a method for scaffold hopping transformations via alchemical free energy calculations, which broaden the usage of such approaches in lead modification and optimisation [ 370 ].…”