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

Perspective pubs.acs.org/jmc How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets Bradley C. Doak, Jie Zheng, Doreen Dobritzsch, and Jan Kihlberg* Department of ChemistryBMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden *S Supporting Information 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. 1. INTRODUCTION with “traditional” small molecule drugs,11 i.e., drugs that comply Drug discovery is at a crossroads where ground-breaking with the rule of 5 (Ro5) guidelines and are highly likely to be advances in our understanding of how diseases develop are now cell permeable and orally bioavailable. Still, it has been pointed made at an unprecedented pace. However, efficiency of drug out that large portions of well-established target classes such as discovery has continued to decline as the number of new drugs ion channels, GPCRs, and nuclear receptors remain unex- plored.10 However, an even larger number of targets from less approved each year has essentially been constant during the “ ffi ” past 30 years, while the costs of pharmaceutical development explored and novel classes which are di cult-to-drug using − fi have increased dramatically.1 3 This decline has been attributed Ro5 compliant compounds could provide signi cant, additional to a few fundamental issues, including a need to deliver first-in- opportunities for drug discovery. For example, the human proteome8,9 is estimated to have 100 000−1 000 000 binary class treatments for complex diseases while at the same time − 12,13 meeting increased demands for safety and efficacy.4 As a result protein protein interactions (PPIs) and may constitute there is high attrition in phase II and III clinical trials, mainly one of the most important sources of novel targets for drug due to lack of efficacy and safety issues.2,5,6 Therefore, it has discovery. However, the proportion of the proteome and its been emphasized that improved selection of targets that are massive number of PPIs that are involved in pathogenic mechanisms remains to be established. Even with that caveat associated with diseases is the single most important factor fi required to increase efficacy and deliver innovative medicines.2 the recent and rapid developments in target identi cation urgently need to be matched by innovative approaches for During the past two decades the human genome and various 14,15 other genomes have been mapped,7 and significant progress has modulating nontraditional target classes, such as PPIs. fi “ ffi ” been made toward mapping the human proteome.8,9 These Targets currently classi ed as di cult-to-drug with Ro5 rapid advances have made an increased number of potential compliant ligands characteristically have binding sites that are fl fl drug targets accessible that belong to both established and large, highly lipophilic, or highly polar, exible, at, or novel target classes. Despite the advances in target featureless (i.e., contain few opportunities for molecular fi interactions such as hydrogen bond donors and accept- identi cation, less than a quarter of recently approved drugs 16−19 are directed against novel targets, and the majority of these ors). In addition, the perceived lack of oral bioavailability drugs target established classes of G protein-coupled receptors outside Ro5 space has led many to abandon these targets and “ ” (GPCRs), transporters, or enzymes.1,10 A limiting factor may classify them as undruggable . Thus, what initially appears as be that approximately 3000 of the genes in the human genome have been estimated to be related to disease. Out of these only Received: August 18, 2015 600−1500 have been considered amenable for manipulation Published: October 12, 2015 © 2015 American Chemical Society 2312 DOI: 10.1021/acs.jmedchem.5b01286 J. Med. Chem. 2016, 59, 2312−2327 Journal of Medicinal Chemistry Perspective vast opportunities of novel targets emerging from advances in two data sets having mean quantitative estimates of druglike- genomics and proteomics will, to a large extent, require small ness (QED) scores of 0.31 and 0.16, respectively, providing a molecule drug discovery to move outside Ro5 space into what single measure of the distance from traditional rule of 5 space. has been termed beyond Ro5 (bRo5) or “middle space”.20 Both of these QED scores are significantly below 0.67 and 0.49, Interestingly, recent analysis of drugs and clinical candidates which are the mean values identified by medicinal chemists for that fall outside Ro5 space has shown that this space offers compounds being “attractive” and “unattractive” for drug significant possibilities for discovery of orally bioavailable and development, respectively.21,30 Our data set of drugs and cell permeable compounds, possibly more than previously clinical candidates was obtained by searching different data- thought.21 It can therefore be argued that a too strict bases for compounds with MW ranging from 500 to 3000 Da implementation of the Ro5 may have hampered the followed by filtering to remove contrast agents, veterinarian pharmaceutical industry from seizing opportunities involving products, etc.21 Therefore, some drugs and clinical candidates − novel but more difficult targets.21 25 outside our strict definition of Ro5 space, i.e., those with MW < We and others have hypothesized the benefits of using bRo5 500 Da and one of HBD > 5, HBA > 10, ClogP > 5, or ClogP < drugs for difficult targets,14,15,21,26,27 and examples and case 0, have not been included in the analysis. We also highlight that studies have been reported in the literature. Here we present a some calculated properties are highly correlated to each other − comprehensive analysis of bRo5 drugs and clinical candidates (e.g., HBA and PSA, rs = 0.89 0.94), as illustrated in the that highlight their ability to modulate difficult targets, thereby correlation tables and principle component analysis, which can expanding the number of targets for which we can design oral be found in the Supporting Information (Figures S1 and S2).It and parenteral drugs. First, we assessed what target classes is nonetheless useful to base the classification on these current drugs and clinical candidates outside Ro5 space are seemingly redundant properties to aid filtering and analysis in directed toward in comparison to Ro5 compliant drugs. different situations, ranging from computer assisted to practical, Analysis then focused on how drugs and clinical candidates “back of the envelope” calculations. The three data sets were outside Ro5 space bind to their targets based on crystal then analyzed and compared extensively across different structures of 130 clinically relevant complexes, which were ligand−target interaction properties. Differences are described compared to drug−target complexes in Ro5 space. This as being “significant” where statistically significant different allowed us to define to what extent binding site and ligand mean values were found (unpaired t test, with a p-value of characteristics such as size, shape, molecular interactions, <0.05); full details and p-values can be found in the Supporting affinity, and ligand efficiencies differ between different drug Information but are also denoted in the figures. spaces. The influence of conformational flexibility of the ligand The data set of 475 drugs and clinical candidates in eRo5 and and its shape was also investigated for compounds in beyond bRo5 space that make up the current data set was previously Ro5 space. The results are then discussed to provide guidance curated and used to investigate oral bioavailability in eRo5 and for design of bioactive small molecule drugs outside Ro5 space bRo5 space.21 It was also classified with regards to chemical for difficult targets. class, route of administration, and phase of development.21 This allows discussion of trends in drug development and 2. DRUGS AND CLINICAL CANDIDATES DATA SETS demonstrates that de novo designed compounds are in majority To facilitate this in-depth analysis of how drugs and clinical (43%), with equal numbers of natural products and peptides/ candidates that do not comply with the Ro5 bind to their peptiodomimetics (26% each) across the full data set.21 The targets, a comprehensive data set of 475 drugs and clinical majority of de novo designed compounds are oral (64%), candidates with MW > 500 Da was classified by the whereas natural products and in particular peptides/peptidomi- compounds’ calculated physicochemical properties. They were metics are mainly parenteral (59% and 80%, respectively). then divided into two data sets where intuitive and natural Analyzing the data set by phase of development, chemical divisions in the ligand property distributions appeared as space, and chemical class demonstrates that de novo designed previously reported,21 each representing different chemical compounds dominate strongly in all clinical phases in eRo5 spaces (Figure 1a). Two data sets of Ro5 compliant drugs were space and that the majority of them are intended for oral also compiled from ChEMBL28 and the recent literature10 for administration (Figure 1b).

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