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Intramolecular Hydrogen Bond Expectations in Medicinal Chemistry Fabrizio Giordanetto,*,† Christian Tyrchan,‡ and Johan Ulander§ †
D.E. Shaw Research, 120W 45th Street, New York, New York 10036, United States Medicinal Chemistry, Respiratory and Inflammation, Innovative Medicines and Early Development Biotech Unit, Astrazeneca, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden § Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, Astrazeneca, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden ‡
S Supporting Information *
ABSTRACT: Design strategies centered on intramolecular hydrogen bonds are sometime used in drug discovery, but their general applicability has not been addressed beyond scattered examples or circumstantial evidence. A total of 1053 matched molecular pairs where only one of the two molecules is able to form an intramolecular hydrogen bond via monatomic transformations have been identified across the ChEMBL database. These pairs were used to investigate the effect of intramolecular hydrogen bonds on biological activity. While cases of extreme, conflicting variation of effect emerge, the mean biological activity difference for a pair is close to zero and does not exceed ±0.5 log biological activity for over 50% of the analyzed sample. KEYWORDS: Intramolecular hydrogen bond, conformation, molecular design, matched molecular pair
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not compatible with the formation of IMHB via classic medicinal chemistry transformations: (a) capping of the hydrogen bond donor atom (HBD), (b) removal of the HBD, or (c) removal of the hydrogen bond acceptor atom (HBA). In order to minimize confounding effects deriving from large structural alterations, we targeted monatomic transformations such as methyl addition to HBDs and oxygen or nitrogen to carbon permutations in the cases of HBD and HBA removals. Each MMP was further annotated with relevant biological target and activity information on type “binding”, as defined in ChEMBL. The aim was to focus as much as possible on the interaction between compound and target as opposed to more complex read-outs of functional or toxicological nature. Only results originating from multiple compound concentrations-response experiments in a nonhigh throughput screening (HTS) format were considered (see Supporting Information for additional details). This resulted in a total of 1053 MMPs of which 592 were structurally unique. Four hundred and three unique molecular targets are covered by the present data set, spanning a wide range of protein systems including ion channels, transporters, G-protein coupled receptors, enzymes, and nuclear hormone receptors among others. Pseudo six-membered ring MMPs represent the vast majority of the sample (93%), reflecting the higher share of molecular topologies with >70% frequency of IMHB occurrence13 of such ring size. Eighty-four percent of the present data set is represented by only three topologies (i.e., aC3cC3a, 46%; aNaC3a, 28%; and aC3cC3aC3a, 10%). The most frequent
ntramolecular hydrogen bonds (IMHBs) play an essential role in biochemistry and chemistry. They affect the electronic distribution, molecular geometry, shape, and conformation of systems as diverse as proteins, nucleic acids, catalysts, and materials. As such, IMHBs greatly impact molecular properties, function, and interactions.1−5 For these reasons, the formation or disruption of IMHBs is used by medicinal chemists to modulate biological and chemical properties of interest. As an example, the bioactive conformation of a given ligand could be stabilized by IMHBs. This could reduce the conformational and translational entropy upon binding and result in stronger association.6−9 Furthermore, the accessibility of polar atoms in a molecule could be decreased if IMHBs are established. This may influence desolvation equilibria and facilitate the passage of molecules through low dielectric environments.10−12 While geometric preferences for the formation of IMHBs have been described based on experimental evidence,13 the presence of stabilizing IMHBs are normally debated based on thermodynamics grounds, especially in high dielectric environments. Furthermore, the effects originating from the formation or disruption of IMHBs have been difficult to predict from structure, increasing the uncertainty in robustly utilizing IMHBs as a design concept. The present study attempts to evaluate the impact of IMHBs on biological activity as a commonly used in vitro optimization variable. We mined ChEMBL14 to identify molecular matched pairs (MMPs) by focusing on molecular topologies with highest frequency of IMHB occurrence (>70%), as described by Kuhn et al.13 Here, we systematically identified MMPs where the second molecule had a structure © XXXX American Chemical Society
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Figure 1. Box plots of the activity difference for the IMHB MMPs. Yellow boxes indicate the interquartile range, horizontal lines define median values, and outliers are depicted as green circles. The data are presented as a whole and subdivided according to the size of the pseudo ring, the chemical transformation within a MMP, and the corresponding IMHB atom pair and its topology. The number of MMPs in each sample is highlighted at the top of each box plot. Dashed blue lines indicate ±0.5 log(activity) values.
IMHB pair is given by a carbonyl and NH group as HBA and HBD, respectively (33%), followed by carbonyl−hydroxyl (25%), heterocyclic nitrogen−NH (23%), and alkoxy−NH (18%). Removal of a HBD via carbon replacement of the corresponding heteroatom or its capping with a methyl group are the most recurrent molecular transformations (36% and 28%, respectively). Interestingly, removal of nitrogen HBD via oxygen or of a HBA via carbon replacement of the corresponding heteroatoms are observed less frequently (20% and 16%, respectively). The fewer observations for the HBA removal transformation reflect the reduced share of heterocyclic nitrogen−NH and alkoxy−NH pairs, as no carbonyl was found transformed to a terminal olefin in the current data set. The distribution of the difference in biological activity between the two molecules in the IMHB pairs studied here is shown in Figure 1. The average and median values for the change in biological activity across the whole data set are −0.05 and 0.0, respectively, and reflect an overall symmetric distribution (Skewness, 0.14; Kurtosis, −0.11). Fifty-three and 88% of the current MMPs display bioactivity differences within ±0.5 and ±1.5 log units, respectively. These results do not significantly change when the size of the pseudo ring formed by the IMHB, the molecular transformation that differentiates the compounds in a MMP or the IMHB atom pairs, is considered. Molecular topologies display greater variability in the bioactivity change with aC3cC3aC3a having the least centered median (0.4 log units), although the paucity of observations and the congeneric chemical nature of the pairs observed for some of these subgroups do not allow for robust extrapolations to be made. While in general the bioactivity difference does not systematically and significantly deviate from ±0.5 log unit, it is interesting to note the recurrent presence of outliers at both tails of the various distributions totaling to more than 25% of the whole sample (N > 200). This indicates that the formation (or removal) of an IMHB can still have a significant impact on the biological activity independently from the IMHB features listed here. Importantly, owing to the symmetrical nature of the distributions, no significant enrichment in positive or negative outliers has been observed, implying that substantial increase
and reduction in biological activity are equally probable. These results are consistent with earlier MMP-based analysis of substituent effects in medicinal chemistry.15 Figure 2 highlights a selection of bioactivity change outliers spanning different target classes, molecular topologies, transformations, and IMHB atomic pairs (see Table S3 in the Supporting Information for the original references). Inspection of the outliers in this study proved very stimulating. For instance, it provides pattern recognition opportunities and molecular design inspiration to medicinal chemists and machine learning methods. Perhaps more importantly, it is a sober reminder of the impact that minimal chemical modification can have on biological activity, even when taken outside of the IMHB context discussed here. Outlier examples span agrochemical (e.g., acetolactate synthase (ALS) inhibitors as herbicides) and pharmaceutical (JNK-1 inhibitors as antineoplastic agents) research, reinforcing the fundamental role of IMHB in nature, independently of the application field. An important limitation of the present analysis is the lack of experimental validation for the majority of the IMHBs studied, as in the case of transmembrane proteins such as the cyclic nucleotide-modulated channel HCN1, the adenosine 2a receptor (A2AAR), and the serotonin isoform 4 receptor (5-HT4R). Here, the replacement of a HBA ether oxygen with a methylene, supposedly disrupting the potential IMHB and resulting in a HCN1 inhibition reduction of 3.8 log unit is particularly fascinating.16 Intriguingly, 65% of the MMPs in the same IMHB topology, pair, and transformation class (N = 24, of which 14 unique) do not result in bioactivity changes greater than ±1 log unit. Likewise, the TIE-2, c-Met, and NS5B inhibitor MMPs listed in Figure 2 make a compelling case for structural information as an enabling factor in IMHB-based design, affording −2.9−4.3 log unit changes in activity. It is noteworthy that the bioactive conformation is strengthened by IMHBs in the TIE-217 and c-Met18 cases, while it is completely disrupted in the NS5b MMP,19 further substantiating the specificity character of IMHBs. The present analysis suggests that forming or disrupting an IMHB via minimal structural modifications will result in less B
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Figure 2. Representative IMHB MMPs outliers defined as Δlog(bioactivity) > 1.5 × interquartile range. IMHB topologies and atomic pairs are highlighted in bold.
molecules of interest are essential prerequisites toward the
than 0.5 log units change of biological activity more than half of the time. The general lack of directionality in the biological activity change and the occurrence of positive and negative outliers highlight the difficulty in generalizing the effect of IMHB on biological activity, as IMHB stem from specific electronic, conformational, and environmental constraints. Despite the obvious limitations of inferring IMHBs based on molecular topologies and using biological data sources of likely different variability, the current data reinforce the notion that IMHB-mediated effects are highly context-dependent. Awareness of the underlying factors affecting IMHBs and the availability of case-specific structural information on the
fruitful exploitation of IMHBs in molecular design.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00002. Materials and methods and supplementary tables (PDF) C
DOI: 10.1021/acsmedchemlett.7b00002 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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AUTHOR INFORMATION
Corresponding Author
*Tel: +1 (212) 478 0822. E-mail: fabrizio.giordanetto@ deshawresearch.com. ORCID
Fabrizio Giordanetto: 0000-0001-9876-9552 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. The authors declare no competing financial interest.
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