How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets

Abstract

To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.

Drug discovery beyond the rule of 5 - Opportunities and challenges

“…Recent reviews have emphasized that target classes that have difficult large, flat, or groove-shaped binding sites such as protein-protein interactions (PPIs), proteases, transferases, and some other nontraditional drug targets may preferentially be modulated by compounds in chemical space beyond the Ro5 (bRo5, Figure 1(a)) [3][4][5]. For example, a number of prominent oral drug classes used as antibacterials, antivirals, antifungals, immunosuppressants, and anticancer agents exist in bRo5 space.…”

“…For example, a number of prominent oral drug classes used as antibacterials, antivirals, antifungals, immunosuppressants, and anticancer agents exist in bRo5 space. Macrocycles provide unique advantages to modulate targets that have flat or shallow groove-shaped binding sites [3,5]. In addition, rod-shaped non-macrocyclic compounds in bRo5 space are ideal for binding to large grooveshaped binding sites, for instance those of PPI [4].…”

“…In addition, rod-shaped non-macrocyclic compounds in bRo5 space are ideal for binding to large grooveshaped binding sites, for instance those of PPI [4]. Independent of their chemotype, oral drugs in bRo5 space may bury up to 800-900 Å 2 of ligand surface area when binding to their target, that is, a surface area approaching that of a PPI interface [3,5]. Just as regular Ro5 compliant drugs, drugs in bRo5 space usually display a K d /IC 50 of 1-100 nM for binding to their targets.…”

“…Just as regular Ro5 compliant drugs, drugs in bRo5 space usually display a K d /IC 50 of 1-100 nM for binding to their targets. Consequently, they usually have lower ligand efficiencies when binding to flator groove-shaped sites than traditional Ro5 compliant drugs binding to pockets or internal sites; an observation that should be kept in mind when prioritizing ligands for difficult targets [5]. Importantly, the physicochemical nature of bRo5 drugbinding interfaces are similar to the surface of the compounds as a whole, and to the surface of Ro5 compliant drugs, suggesting that the same approaches for property-based lead optimization can be used in both chemical spaces [3,5].…”

“…However, a strict implementation of the Ro5, or alternative metrics, has sometimes caused a reluctance to explore novel chemical space where important drug discovery opportunities exist. This may be of particular concern for intracellular targets with large, flat, or groove-shaped binding sites that are unable to be modulated with Ro5 compliant compounds, but can be drugged by orally available and cell permeable compounds in bRo5 space, such as macrocycles [3,5,6]. Very flexible or unstructured targets are still far from being drugged in a rational way by small molecules and may require completely novel approaches such as interference at the expression/RNA level or tagging the target protein for degradation [16].…”