Two‐ and Three‐dimensional Rings in Drugs

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.

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

“…47−52 On one hand, 3D-shaped fragments have been suggested to be capable of sampling a larger chemical space 50 and of exploring the pocket space of targets more extensively than 2D-shaped fragments, 48 being more likely to deliver biologically active and clinically relevant molecules. 51,52 On the other hand, 3D-shaped fragments have raised questions about the implications that their implicit higher molecular complexity can have for hit rates 53 and for ease of synthesis and derivatization. 54 It has also been shown that three-dimensionality can be introduced, to different degrees depending on the connectivity of the fragment scaffold, during fragment elaboration.…”

Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C‐terminal Inhibitors

“…[18] As a flexible structure, the saturated ring system has the ability to adopt multiple conformations and to project substituents into optimal orientations within the binding pocket. Therefore, optimization of the core began by replacement of the A- and/or Bring of the biphenyl core with a saturated ring system.…”

The Isoxazole Ring and Its N‐Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics

“…[38,39] 2.1. [44] The alignment of drug-like properties and selectivity remains am ajor challenge. [40] It is known that the chemical structure of ad rug correlates with its physicochemical properties, i.e.,i ts drug metabolism pharmacokinetics /a bsorption, distribution, metabolism, and excretion-toxicity (DMPK/ADMET) profile, pertaining to Lipinski's rules [41] and ultimately its pharmacological activity.…”