Quest for the Rings. In Silico Exploration of Ring Universe To Identify Novel Bioactive Heteroaromatic Scaffolds

Abstract

Bioactive molecules only contain a relatively limited number of unique ring types. To identify those ring properties and structural characteristics that are necessary for biological activity, a large virtual library of nearly 600 000 heteroaromatic scaffolds was created and characterized by calculated properties, including structural features, bioavailability descriptors, and quantum chemical parameters. A self-organizing neural network was used to cluster these scaffolds and to identify properties that best characterize bioactive ring systems. The analysis shows that bioactivity is very sparsely distributed within the scaffold property and structural space, forming only several relatively small, well-defined "bioactivity islands". Various possible applications of a large database of rings with calculated properties and bioactivity scores in the drug design and discovery process are discussed, including virtual screening, support for the design of combinatorial libraries, bioisosteric design, and scaffold hopping.

Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry

“…A number of studies have analyzed diversity based on the ring systems in structures. [5][6][7][8][9][10][11] 10.1021/jo8001276 CCC: $40.75  2008 American Chemical Society is that structures having such features in common often belong to the same chemical family.…”

De novo branching cascades for structural and functional diversity in small molecules

“…With this planning, reaction conditions were optimized (Supplementary Table 1) for an in situ generation of the nitrone (10) by addition of phenyl hydroxylamine (7) to dimethyl acetylenedicarboxylate (DMAD) (8), and followed by a [3 þ 2] cycloaddition with allene ester (2), leading to azepinone 11 (de novo cascade I, Fig. 3a).…”

“…We compared the molecular shape diversity of our library with established reference sets of 20 top-selling brand name drugs and 20 diverse natural products ( Supplementary Figs 6 and 7). PMI were calculated using Molecular Operating Environment, MOE software package, after minimization of energy of each molecule using a MMFF94x force field with the generalized Born solvation model; eps ¼ r, cutoff [8,10] and gradient ¼ 0.1 RMS Kcal mol À 1 A À 2 . The PMI and related calculations are performed in units of daltons (AMU) and angstroms.…”

“…Probe and drug discovery research, therefore, beseech quality-based compound libraries rich in structural diversity 4,5 . The latter in turn is primarily determined by the number of diverse scaffolds or chemotypes that represent a compound library [6][7][8] . Consequently, new synthetic challenges have emerged aiming at divergent access to structurally distinct and complex scaffolds [9][10][11] .…”

Mild and Rapid Pd‐Catalyzed Cross‐Coupling with Hydrazine in Continuous Flow: Application to the Synthesis of Functionalized Heterocycles

“…These heterocyclic motifs are prevalent structural elements in numerous compounds of significant biological/medicinal value. [5] Among current strategies to generate arylhydrazines, nucleophilic aromatic substitution to an aryl halide (ArX) [6] or diazotization of an aniline followed by reduction of the diazonium salt [7] have long been preparative methods of choice [Eq. (1)].…”