The Relationship Between Target-Class and the Physicochemical Properties of Antibacterial Drugs ⇑ Grace Mugumbate, John P
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CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Bioorganic & Medicinal Chemistry 23 (2015) 5218–5224 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc The relationship between target-class and the physicochemical properties of antibacterial drugs ⇑ Grace Mugumbate, John P. Overington European Molecular Biology Laboratory—European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, United Kingdom article info abstract Article history: The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept Received 30 January 2015 that antibacterial drugs occupy a differentiated region of physicochemical space compared to human- Revised 20 April 2015 targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower logP and Accepted 22 April 2015 higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved Available online 28 April 2015 drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e., composed of a complex of RNA and protein) fall outside the conventional human ‘drug-like’ chemical Keywords: space; whereas antibacterials that modulate bacterial protein targets, generally comply with the ‘rule- Antibacterials of-five’ guidelines for classical oral human drugs. Our analysis suggests a strong target-class association Physicochemical properties Drug targets for antibacterials—either protein-targeted or riboprotein-targeted. There is much discussion in the liter- Ribosome ature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our anal- ysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery. Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction together cause close to a million deaths every year.5,6 To curb the development of resistance to rifampicin, multidrug therapy The discovery of antibacterial agents, such as the aminoglyco- (MDT) is often used, where the drug is used in combination with sides, streptogramins, tetracyclines, b-lactams, and quinolones, other antibacterials. MDT has been successful as evidenced by from the 1930s onwards1 brought significant relief to the health the decrease in the number of reported leprosy or TB cases but it burden caused by pathogenic bacteria worldwide. Nevertheless, increases the drug burden on the patient, and could lead to non- the success of antibacterial chemotherapy is now being signifi- compliance and the eventual emergence of resistance. In the indus- cantly challenged by the emergence of drug-resistant bacterial trialised Northern hemisphere drug resistance, for example with strains, poor hit rates from genomics/target-led screens2 and high hospital-acquired methicillin-resistant Staphylococcus aureus drug failure rates in late clinical development.3 Treatment of bac- (MRSA), is also perceived as a major societal threat. The aforemen- terial infectious diseases is also often complicated by comorbidity, tioned challenges call for continual discovery and development of for example, co-infection with human immunodeficiency virus new mechanism differentiated antibacterials. These drugs would (HIV), extended duration of chemotherapy and diagnostic delays.4 potentially be less prone to resistance (or at least have Drug-resistant strains have a direct impact on the clinical treat- distinguished resistance profiles), have new modes of action and/or ment of diseases such as leprosy, Staphylococcus, Strepto- and targets and with the capability to reduce drug load. Enterococcus, Clostridia, and Pseudomonas, and arguably most sig- Advances in technologies in genomics and sequencing, high- nificantly on tuberculosis (TB). throughput screening (HTS), automated chemical synthesis and Tuberculosis and leprosy are mycobacterial diseases affecting structural biology, have so far had limited direct impact on the dis- substantial parts Africa, the Americas, South-East Asia, the covery of new classes of drugs; it has taken more than four decades Eastern Mediterranean and the Western Pacific Regions and for the novel linezolid class of antibacterial drugs (2000), to be approved7,1, and more recently bedaquiline (2012) for treatment of drug-resistant tuberculosis.8 This productivity challenge has ⇑ Corresponding author. Tel.: +44 (0) 1223 494467. drawn researchers in industry and academia, and more recently E-mail address: [email protected] (J.P. Overington). http://dx.doi.org/10.1016/j.bmc.2015.04.063 0968-0896/Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). G. Mugumbate, J. P. Overington / Bioorg. Med. Chem. 23 (2015) 5218–5224 5219 funding agencies and public bodies, to propose and develop new proteins or riboproteins and non-antibacterials targeting specifi- approaches to antibacterial discovery. Examples include identifica- cally human proteins, using analysis routines implemented in tion of whole cell-based methods to identify antibacterial leads with Pipeline Pilot (Biovia).18 The goal was to determine the association the ability to penetrate the bacterial cell wall, in conjunction with of physicochemical properties of antibacterials and their target- currently used target-based approaches. Furthermore, the consider- class. Bioactive compounds that target human proteins generally ation of the physicochemical properties of the chemical compounds fall within the established parameter range for Lipinski ‘drug-like’ during the early stages of drug discovery process9,1,10 has helped to compounds and were therefore used as comparator benchmarks. avoid failure in Phases II/III of clinical development. Experimental and computational approaches have therefore been used to analyse 2. Methods the historical physicochemical properties of drugs and to develop models used in determining drug-like compounds, and in some 2.1. Source of target-ligand pairs cases, propose biased or focussed properties for antibacterials.11 Study of the properties of approved drug structures in the All compound and target data used in this work was obtained 1990’s led to the concept of a restricted range of physicochemical from the ChEMBL database19,20 an Open Access database of bioac- parameters that appeared optimal for orally administered drugs— tive small molecules and activity data. ChEMBL version 19, holds 12 many researchers have used the ‘rule of five’ as a guide for 1.4 million distinct bioactive small molecules, 10 thousand ‘drug-like’ compounds during screening and structure modification annotated targets, and more than 12 million activities. The data of leads to optimise their potency, metabolism and exposure. The has been manually extracted from about 57,000 publications and ‘rule of five’ states that good absorption is more likely when an curated by experienced chemistry and biology curators. orally administered compound has less than five hydrogen-bond donors, molecular weight <500 Da, clogP <5, and less than 10 2.2. Drugs and their targets dataset hydrogen-bond acceptors.12,13 Later it was also observed that polar surface area (PSA) and alogP could predict with 95% confidence A dataset containing more than 1700 drugs including bioactiv- that a test compound would have high or low (90% or 30%, ity information was retrieved from ChEMBL version 19 using a respectively) intestinal absorption in humans.14 For high absorp- Pipeline Pilot protocol (Biovia).18 An SQL query was written to pull tion the upper limits were, PSA 131.6 Å2, and alogP of 5.88. out information for distinct approved drugs and their annotated Veber et al.15 suggested that compounds with 10 or less rotatable targets. The criteria used included extraction of simple drug mole- bonds and PSA less than or equal to 140 Å2 (or 12 or fewer hydro- cules that were approved drugs, and had a specified therapeutic gen-bond donors or acceptors) would have good oral availability in application (therapeutic flag 1). rats. A number of authors subsequently reported that approved antibacterial agents often violated Lipinski’s ‘rule of five’, with antibacterials occupying a different region of physicochemical 2.3. Physicochemical properties and analysis space7,9,16, some of which are dosed parenterally or topically and are more polar and have high aqueous solubility.8 The dataset was split into two, the first subset consisted of Recently the physicochemical space of antibacterials has been drugs that act through human targets and the second one had classified based on bacteria classes by O’Shea et al.7 For 147 active those that act through bacterial targets. The bacterial target subset antibacterial compounds analysed, it was shown that Gram-posi- was further divided into two specific sub-subsets; namely (i) bac- tive and Gram-negative antibacterials have different physicochem- terial-proteins (where the molecular target is a simple