Hit Identification and Binding Mode Predictions by Rigorous Free Energy Simulations

Abstract

The identification of lead molecules using computational modeling often relies on approximate, highthroughput approaches, of limited accuracy. We show here that, with a methodology we recently developed, it is possible to predict the relative binding free energies of structurally diverse ligands of the estrogen receptor-R using a rigorous statistical thermodynamics approach. Predictions obtained from the simulations with an explicit solvation model are in good qualitative agreement with experimental data, while simulations with implicit solvent models or rank ordering by empirical scoring functions yield predictions of lower quality. In addition, it is shown that free energy techniques can be used to select the most likely binding mode from a set of possible orientations generated by a docking program. It is suggested that the free energy techniques outlined in this study can be used to rank-order, by potency, structurally diverse compounds identified by virtual screening, de novo design or scaffold hopping programs.

Perspective: Alchemical free energy calculations for drug discovery

“…Michel et al used dual-topologies to compute the relative free energy between different potential binding modes of the same ligands, 107,108 highlighting the fact that adequate sampling over binding modes is not guaranteed, nor is the binding mode always obvious. Here, subtle differences in ligand composition could easily alter the binding mode, 107 and stable binding modes differed by 1 kcal/mol 107 to 7 kcal/mol.…”

“…Here, subtle differences in ligand composition could easily alter the binding mode, 107 and stable binding modes differed by 1 kcal/mol 107 to 7 kcal/mol. 108 One other study of particular interest highlighted multiple binding modes of catechol-O-methyltransferase inhibitors which had to be treated separately in relative calculations because of time scale issues.…”

Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field

“…1,5,8,[16][17][18][19][20] However, it has not been demonstrated that highly accurate results can be achieved reliably across a wide range of ligands and protein targets, as would be needed for the method to be useful in industrial pharmaceutical research programs.…”

Separated topologies—A method for relative binding free energy calculations using orientational restraints

“…In the dual topologies approach, the computational morphing process carries along two ligand molecules at the same time throughout all simulations. [14][15][16] Using this method, the simulations begin with both a "real" ligand A and a "dummy" ligand B, and over the course of the alchemical transformation, A becomes the dummy ligand while B becomes the real ligand. That is, in the initial state the non-bonded interactions of B are fully decoupled from the rest of the system (the protein and the solvent) and in the final state the nonbonded interactions of A are fully decoupled.…”

“…16 Other methods use constraints--non-energetic terms which are enforced at each timestep-to connect A and B, in some instances by performing identical MC moves on both ligands. 14,15 Restraints which connect A to B do not alter the rotational and translational entropy of either ligand in the fully coupled state, because even though the fully coupled A is always attached to B, B does not interact with the environment and thus does not alter the free energy landscape felt by A.…”