Exploring the chemical space and the bioactivity profile of lactams: a chemoinformatic study

Abstract

Lactams are a class of compounds important for drug design, due to their great variety of potential therapeutic applications, spanning cancer, diabetes, and infectious diseases. So far, the biological profile and chemical diversity of lactams have not been characterized in a systematic and detailed manner. In this work, we report the chemoinformatic analysis of beta-, gamma-, delta- and epsilon-lactams present in databases of approved drugs, natural products, and bioactive compounds from the large public database ChEMBL. We identified the main biological targets in which the lactams have been evaluated according to their chemical classification. We also identified the most frequent scaffolds and those that can be prioritized in chemical synthesis, since they are scaffolds with potential biological activity but with few reported analogs. Results of the biological and chemoinformatic analysis of lactams indicate that spiro- and bridged-lactams belong to classes with the lowest number of compounds and unique scaffolds, and some showing activity against specific targets. Information obtained from this analysis allows focusing the design of new chemical structures in less explored spaces and with increased possibilities of success.

Fig. 1. Selected examples of biologically active β- (a), γ- (b), δ- (c) and ε-lactam (d) containing molecules.

Fig. 2. Substructures defined for the identification and classification of lactams in β-, γ-, δ- and ε-lactams, which are further classified as fused- (a), spiro- (b), isolated- (c) and bridged- (d) lactams.

Fig. 3. Percentage of β-, γ-, δ- and ε-lactams, which are further classified as isolated-, bridged-, fused-, and spiro-lactams in the databases of approved drugs, natural products, and ChEMBL.

Fig. 4. Visual representation of the chemical space: (a) principal component analysis of six physicochemical properties of pharmaceutical interest: molecular weight, hydrogen bond donors, hydrogen bond acceptors, the octanol and/or water partition coefficient, topological polar surface area, and number of rotatable bonds. (b) Principal Moment of Inertia (PMI) plot. The top left-hand corner of the PMI represents compounds with rod-like features (e.g., acetylene), the top right corner represents compounds with spherical features (e.g., adamantane), and the bottom corner represents compounds with disc-like features (e.g., benzene).

Fig. 5. Pie charts summarizing the biological targets with the highest number of active lactam compounds. (a) Human targets, (b) non-human targets. The targets are grouped according to the type of target reported in ChEMBL. Compounds with a pIC₅₀ greater than 6 (<1000 nM) and percentage of inhibition greater than 60% were considered as active compounds.

Fig. 6. Biological profile of data sets of lactams with more than 50 compounds tested in human targets. The lactams are grouped according to their chemical classification (Fig. 2) and the targets are grouped according to their classification in ChEMBL. The size of each dot indicates the relative number of compounds. The colors of the data points denote the percentage of active compounds using a continuous scale (red, a lower percentage and green, a higher percentage). PF: protein family, PPI: protein–protein interaction.

Fig. 7. SAR of lactams tested against bromodomain 4. The compounds are grouped according to their chemical classification, and the value of −log IC₅₀ is shown with colors (in green the least active and in blue the most active compounds). The most similar neighbors to consider for each molecule were calculated in DataWarrior by a rubberbanding forcefield approach.

Fig. 8. Chemotype enrichment plot. The abscissa indicate the enrichment factor (EF) as defined by eqn (1). Background activity is indicated by the vertical dashed line at EF = 1. The ordinate indicates the chemotype frequency in the database. Background frequency is indicated by the horizontal dashed line at frequency = 20. To facilitate the view, only scaffolds with EF up to 20 are displayed. Each of the data points in the figure corresponds to a chemotype that are further distinguished in color by class. The structure of the highlighted scaffolds can be seen in Fig. 9a.

Fig. 9. (a) Scaffolds most frequents with EF greater than 1. (b) Less frequent scaffolds with EF greater than 1. The scaffold ID is indicated and in brackets the frequency of that scaffold in the database. Enrichment factors (EF) are shown and the number (n) of total compounds with the scaffold that have been tested against the particular target.