Abstract
Using small, flat aromatic rings as components of fragments or molecules is a common practice in fragment-based drug discovery and lead optimization. With an increasing focus on the exploration of novel biological and chemical space, and their improved synthetic accessibility, 3D fragments are attracting increasing interest. This study presents a detailed analysis of 3D and 2D ring fragments in marketed drugs. Several measures of properties were used, such as the type of ring assemblies and molecular shapes. The study also took into account the relationship between protein classes targeted by each ring fragment, providing target-specific information. The analysis shows the high structural and shape diversity of 3D ring systems and their importance in bioactive compounds. Major differences in 2D and 3D fragments are apparent in ligands that bind to the major drug targets such as GPCRs, ion channels, and enzymes.
Highlights
Aromatic ring scaffolds are often used in medicinal chemistry as they have more robust chemistry than 3D scaffolds
Ring fragment profile Only 65 of 1297 marketed drug molecules have no ring structure, showing how important ring assemblies are in drug skeletons
We carried out this study to analyze 2D and 3D fragments in drugs as well as characterize their molecular profiles, diversity, and target classes
Summary
Aromatic ring scaffolds are often used in medicinal chemistry as they have more robust chemistry than 3D scaffolds. Researchers from GSK [11] suggested that aromatic ring count negatively affects the developability properties of lead compounds, being correlated with lower solubility and higher lipophilicity, along with other undesirable properties. Taken together, these features can potentially lead to poorer efficacy and greater toxicity. Against 100 sequence-unrelated proteins using small-molecule microarrays They found that increasing the content of sp3-hybridized atoms improved binding selectivity and frequency, resulting in improved performance of screening collections [13]. A detailed analysis of the 2D and 3D fragments found in approved drugs, together with their intended protein targets can give further insights to the role of these fragments in drug binding
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