A Survey of Methods for Searching the Conformational Space of Small and Medium‐Sized Molecules

Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike molecules are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compounds entering clinical trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chemistry, we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six-and seven-membered ring systems are discussed. The article closes with a section on attractive sulfuroxygen contacts.

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“…Computational conformational analysis is a central task in molecular design (for a review see ref 1).…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Brameld

Kuhn

Reuter

et al. 2008

J. Chem. Inf. Model.

331

332

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“…47 Since the lowest energy conformer is not necessarily the bioactive conformer, 46 all of the top five conformers of the query tripeptide were evaluated for their suitability as a shape based query model by considering their ability to rank-order the known antagonists. This assumes that all the known antagonists bind at the same site on the same receptor as the query tripeptide.…”

Section: Shape Based Query Using Known Antagonist Of the Grb7-sh2 Domainmentioning

confidence: 99%

Benzopyrazine derivatives: A novel class of growth factor receptor bound protein 7 antagonists

Ambaye

Gunzburg

Lim

et al. 2011

Bioorganic & Medicinal Chemistry

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“…This field had much impetus about 20 years ago, and was reviewed then [50,51]. Since then, conformational sampling techniques have continued to develop and improve [5,8,9,52,53], and invaluable experience has been gained.…”

Section: Introductionmentioning

confidence: 98%

Conformational Sampling and Energetics of Drug-Like Molecules

Foloppe

Chen²

2009

CMC

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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.

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A Survey of Methods for Searching the Conformational Space of Small and Medium‐Sized Molecules

Cited by 110 publications

References 148 publications

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Benzopyrazine derivatives: A novel class of growth factor receptor bound protein 7 antagonists

Conformational Sampling and Energetics of Drug-Like Molecules

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