Chemodiversity and Molecular Plasticity: Recognition Processes as Explored by Property Spaces

Abstract

In the last few years, a need to account for molecular flexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a flexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defines a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure--activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fill this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profiles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences.

Predicting the physicochemical profile of diastereoisomeric histidine‐containing dipeptides by property space analysis

“…The property space of the dipeptides was investigated by calculating the following properties for each conformer stored during the MD simulations in vacuo, in water, and in chloroform: Its radius of gyration, a well‐known descriptor encoding molecular shape and size, and whose variations can be used to estimate molecular flexibility; Its conformer‐dependent log P MLP value (also known as virtual log P, as computed here by the Molecular Lipophilicity Potential (MLP) approach; and Its polar surface area (PSA), which parameterizes their H‐bonding capacity …”

“…These last relations lead to the concept of molecular sensitivity, which encodes the ability of a molecule to modulate its properties by varying its conformational profile. The concept (and the descriptors) of property space found noteworthy applications to analyze the dynamic behavior of both small ligands and large biomacromolecules as recently reviewed …”

“…The concept (and the descriptors) of property space found noteworthy applications to analyze the dynamic behavior of both small ligands and large biomacromolecules as recently reviewed. 16,17 Benchmarking analyses revealed that, on average, 2D methods for log P prediction are largely more accurate than 3D ones. 11 On the one hand, this may confirm that the likelihood of errors usually increases with algorithm complexity.…”

Small Molecules as Exemplars of Emergent Properties and Diversification into the ‘Adjacent Possible’

“…As far as flexibility and conformational space are concerned, four convenient and informative parameters have been established as [36] [71] [72]:…”

“…Sensitivity is also described as the coefficient in a function relating for example conformational space and lipophilicity space [36]. Thus, molecules are said to be sensitive when their log P MLP is markedly influenced by even small conformational changes, whereas the log P MLP of insensitive molecules changes only modestly even during major geometric fluctuations.…”