3D conformation

H. Ramasamy, R. Nambudripad, and T. E. Smith, Al Extended Genetic Algorithm for 3D Conformational Search. 

With the development of accurate computational methods for generating 3D conformations of chemical structures, QSAR approaches that employ 3D descriptors have been developed to address the problems of 2D QSAR techniques, e.g., their inability to distinguish stereoisomers. The examples of 3D QSAR include molecular shape analysis (MSA) [34], distance geometry [35,36], and Voronoi techniques [37]. 

Fig. 9.3. Several mechanisms underlie the functional versatility of the ER. The different distributions of the alpha and beta isotypes of ER conditions a first step that warrants distinct functional profiles depending on the higher or lower affinity of the ligand for one or another isotype (upper panel). Then, differentligands generate distinct 3D conformations in the ligand-receptor complex that condition different interaction profiles with the promoters of target genes (lower panel)...

As illustrated in the next section, the use of biological fingerprints, such as from a BioPrint profile, provides a way to characterize, differentiate and cluster compounds that is more relevant in terms ofthe biological activity of the compounds. The data also show that different in silico descriptors based on the chemical structure can produce quite different results. Thus, the selection of the in silico descriptor to be used, which can range from structural fragments (e.g. MACCS keys), through structural motifs (Daylight keys) to pharmacophore/shape keys (based on both the 2D structure via connectivity and from actual 3D conformations), is very important and some form of validation for the problem at hand should be performed. 

Scheme 3 Synthetic aspects of two conceptually different strategies for the introduction of piperazines via isocyanide based MCRs and two representative 3D conformations of 18A (blue) and 18B (cyan). An intramolecular hydrogen bond in compound 18B was shown in red dots...

Scheme 6 Use of Lewis acid catalyst for 3-CR 2-imino-piperazine synthesis and representative 3D conformations of the cis- and trans-stereoisomer 39 are shown. Two 3D structures of the cis- and trans-stereoisomer 39 are shown...

Scheme 7 Synthesis of 1,6 dihydropyrazine derivatives and two representative 3D conformations...

Scheme 8 Synthesis of a l,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives via the Ugi four-component reaction and two representative 3D conformation of 49A (cyan) and 49B (blue). Yield shown represents yield over all steps...

Scheme 10 Use of a bi-functional W-sulfonyl-iV-(2-oxoproply) glycines for the SCR synthesis of ketopiperazines and two representative 3D conformations of 59A (cyan) and 59B (Mm)...

Scheme 15 Use of both N- and C-protected amino acid to synthesize 2,6 DKPs with two representative 3D conformations of 92A (blue) and 92B (cyan). Yields not reported...

Scheme 16 Two different ways to stereoselectively create 2,5-DKP s via Ugi reaction with two representative 3D conformations of 97 (blue) and 100 (cyan). Yield shown represents yield over ail steps...

Scheme 21 S) thesis of tryptophan derived 2,5-DKPs with two representative 3D conformations of 129A (cyan) and 129B (blue). (PG = Protecting group Fmoc or Boc) Yield shown represents...

Scheme 26 Synthesis of bicyclic diketopiperazines and two representative 3D conformations of...

Scheme 35 Synthesis of 3,4-dihydroquinoxalin-2-amine derivatives 196 and two representative 3D conformations of 196A (blue) and 196C (cyan)...

Commonly used molecular descriptor types are listed. For each category, one or two representative examples are given. Dimensionality refers to the molecular representation (molecular formula, 2D drawing, or 3D conformation) from which the descriptors are calculated (adapted from ref. 4). 

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