Toward accurate relative energy predictions of the bioactive conformation of drugs

Abstract

Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol(-1) of a local minimum, with penalties above 2.0 kcal mol(-1) being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery.

Quantum mechanical binding free energy calculation for phosphopeptide inhibitors of the Lck SH2 domain

“…It is also reasonable to expect that the relaxation energy, a correction to the sin- gle-trajectory approach, will also be positive and small for the ligands 19,62 and for a rigid system such as the SH2 domain. 9 Furthermore, considering the similarity of the studied peptides, the impact of all of these corrections to the relative binding free energy will be negligible.…”

“…In this approach, the internal energy change on binding is neglected, a reasonable approximation considering that the SH2 domain is fairly rigid, 9 and the ligand relaxation energy is usually expected to be small. 19,62 Under these conditions, the single-trajectory approach has been shown to reduce noise in end-point calculations. 19,29,53,63,64 The vacuum energy hUi was calculated as the average over the series of static frames for the complex, protein, and ligand.…”

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

“…However, force field energies are widely subject to variability because of different parameterization and convergence criteria and are frequently overemphasized by the dominance of electrostatic interactions. 29,30 This fact renders energetic ranking of conformers using force field energies complicated at best and clearly suggests a strong measure of caution in FIGURE 6 Representative conformations from the three NAMFIS families for 2R3S D-Ser. From left: best fit (52%), fourth best fit (5%), and sixth best fit (2%).…”

Binding energies of tyrosine kinase inhibitors: Error assessment of computational methods for imatinib and nilotinib binding

“…Entropic and enthalpic contributions were significant. There have been criticisms about the magnitude of ligand conformational energy changes during protein binding [32], based on errors induced by force field calculations being inadequate for calculating energies, and errors in using X-ray data which inaccurately portray conformations, distort ring structures, induce steric clashes etc [16].…”