Iain M. McLay

Traditional methods for performing 3D-QSAR rely upon an alignment step that is often time-consuming and can introduce user bias, the resultant model being dependent upon and sensitive to the alignment used. There are several methods which overcome this problem, but in general the necessary transformations prevent a simple interpretation of the resultant models in the original descriptor space (i.e. 3D molecular coordinates). Here we present a novel class of molecular descriptors which we have termed GRid-INdependent Descriptors (GRIND). They are derived in such a way as to be highly relevant for describing biological properties of compounds while being alignment-independent, chemically interpretable, and easy to compute. GRIND are obtained starting from a set of molecular interaction fields, computed by the program GRID or by other programs. The procedure for computing the descriptors involves a first step, in which the fields are simplified, and a second step, in which the results are encoded into alignment-independent variables using a particular type of autocorrelation transform. The molecular descriptors so obtained can be used to obtain graphical diagrams called "correlograms" and can be used in different chemometric analyses, such as principal component analysis or partial least-squares. An important feature of GRIND is that, with the use of appropriate software, the original descriptors (molecular interaction fields) can be regenerated from the autocorrelation transform and, thus, the results of the analysis represented graphically, together with the original molecular structures, in 3D plots. In this respect, the article introduces the program ALMOND, a software package developed in our group for the computation, analysis, and interpretation of GRIND. The use of the methodology is illustrated using some examples from the field of 3D-QSAR. Highly predictive and interpretable models are obtained showing the promising potential of the novel descriptors in drug design.

The current interest in combinatorial chemistry for lead generation has necessitated the development of methods for design and evaluation of the diversity of the resultant compound libraries. Such methods also have application in selecting diverse sets of compounds for general screening from corporate databases and in the analysis of large sets of structures to identify common patterns. In this paper we describe a novel methodology for calculating diversity and identifying common features based on the three-point pharmacophores expressed by a compound.1 The method has been implemented within the environment of the Chem-X molecular modeling package (ChemDBS-3D), using a systematic analysis of 3D distance space with three point combinations of six pharmacophoric groups. The strategy used to define the pharmacophores is discussed, including an in-house developed atom type parameterization. The method is compared with the related approach being developed into the ChemDiverse module of Chem-X. Results from an analysis of a large corporate database and examples of combinatorial library profiling with both methods are presented. The use of 3D pharmacophores for assessing diversity, and the application of such methods to combinatorial library design, is discussed.

An X-ray crystal structure is reported for the novel enhanced-affinity glucocorticoid agonist fluticasone furoate (FF) in the ligand binding domain of the glucocorticoid receptor. Comparison of this structure with those of dexamethasone and fluticasone propionate shows the 17 alpha furoate ester to occupy more fully the lipophilic 17 alpha pocket on the receptor, which may account for the enhanced glucocorticoid receptor binding of FF.

In this paper we address several issues in the design of lead optimization libraries. Multipharmacophore descriptors were first developed in the context of designing diverse compound libraries. One reason for favoring such descriptors is the importance of the pharmacophore hypothesis in understanding the interaction of a compound with a protein target. Allied to this is the proposal that sampling over all potential pharmacophores leads to diversity in a biologically relevant space. We present results in support of this argument and also demonstrate that such methods are applicable to the design of focused libraries where the aim is to design the library toward a known lead or leads. This portability is important because it means that the same descriptors can be used for diverse library design, screening set selection, and focused library design, giving a consistent approach. We also examine the question of designing libraries with improved pharmacokinetic properties and show that it is possible to derive simple and rapidly computable descriptors applicable to the prediction of drug transport properties. Furthermore, these can be applied in the context of library design, although it may be necessary to synthesize libraries in a noncombinatorial manner to obtain the best results. To address this problem, we describe a Monte Carlo search procedure that allows the selection of a near-combinatorial subset in which all library members satisfy the design criteria. We present an example from our own work that illustrates how consideration of calculated log P, molecular weight, and polar surface area in the design of a combinatorial library can lead to compounds with improved absorption characteristics as determined by experimental Caco-2 measurements.

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.