Conformational Sampling and Energetics of Drug-Like Molecules

Abstract

The pharmacological properties of small organic molecules depend on their three-dimensional (3D) structure. That includes physico-chemical properties (e.g. solubility, partition equilibria) and molecular recognition such as binding to a therapeutic macromolecular target. At physiological temperature, the 3D structure of a flexible small molecules is expected to cover an ensemble of energetically accessible conformations. Therefore, it is of fundamental and practical importance to be able to relate the energetics of a molecule to its conformational preferences and derived properties, a discipline known as conformational analysis. The first step of conformational analysis is the generation of the conformers, referred to as conformational sampling. This is typically performed primarily using computational chemistry methods. Taking a fresh look at these methods for a broad medicinal chemistry audience is the object of the present review. Indeed, conformational sampling methods continue to be developed, improved and tested. They underpin much of the detailed analysis of structure-activity relationships on selected chemical series, but also the preparation of large conformational libraries of generic compounds and their exploitation for virtual screening. In recent years, the conformational models of active compounds have been examined to see how frequently they capture their target-bound bioactive conformation, as revealed by X-ray crystallography. This provided a context to scrutinize the intrinsic conformational energetics of these bioactive conformers, but this subject is still intensely debated. Another line of investigation concerns the conformational diversity of the 3D models, and how well they cover the conformational and pharmacophoric spaces. This review addresses in general terms: i) the basic principles of conformational analysis, including modern computational estimates of intramolecular energy and how those are mapped on the molecular potential energy surface, ii) some experimental contributions to probing of the small molecule conformations, iii) the various computational methods available to generate conformational models, iv) the conformational properties of the bioactive conformers, and v) attempts to quantify the coverage of the conformational models and the controlling parameters.

Computational Methods in Drug Discovery

“…Molecules are flexible in solvent environment and hence representation of conformational flexibility is an important aspect of molecular recognition. Often conformations of protein and ligand are precomputed using simulation or knowledge-based methods (Liwo et al, 2008;Foloppe and Chen, 2009).…”

Multi-Timescale Dynamics Study of FKBP12 Along the Rapamycin–mTOR Binding Coordinate

“…[7][8][9][10] One of the central goals of macromolecular biophysics research is to rationally design drugs that affect aberrant function. While the drug design community has paid much attention to the conformational heterogeneity of unbound drug molecules and how this affects the energetics of binding, 11,12 there are relatively few investigations into how drug binding affects target flexibility. This is important, as drugs exert their therapeutic effects by modulating downstream events such as effector binding or catalysis, and dynamics clearly influences these processes.…”

Prediction of Promiscuous P-Glycoprotein Inhibition Using a Novel Machine Learning Scheme

“…The conformational flexibility of studied molecules was taken into account by creating multiple conformers since three-dimensional conformations of ligands are of critical importance in developing pharmacophore models [55]. As such, all selected molecules were subjected to conformation search to generate the low-lying conformations, which were carried out using the mixed Monte Carlo multiple minimum (MCMM) [56]/low mode [57] by MacroModel (Schrödinger, Portland, OR).…”