Natural products (NPs) are often regarded as sources of drugs or drug leads or simply as a "source of inspiration" for the discovery of novel drugs. We have built the Northern African Natural Products Database (NANPDB) by collecting information on ∼4500 NPs, covering literature data for the period from 1962 to 2016. The data cover compounds isolated mainly from plants, with contributions from some endophyte, animal (e.g., coral), fungal, and bacterial sources. The compounds were identified from 617 source species, belonging to 146 families. Computed physicochemical properties, often used to predict drug metabolism and pharmacokinetics, as well as predicted toxicity information, have been included for each compound in the data set. This is the largest collection of annotated natural compounds produced by native organisms from Northern Africa. While the database includes well-known drugs and drug leads, the medical potential of a majority of the molecules is yet to be investigated. The database could be useful for drug discovery efforts, analysis of the bioactivity of selected compounds, or the discovery of synthesis routes toward secondary metabolites. The current version of NANPDB is available at http://african-compounds.org/nanpdb/ .

Antimicrobial resistance is an emerging global health threat necessitating the rapid development of novel antimicrobials. Remarkably, the vast majority of currently available antibiotics are natural products (NPs) isolated from streptomycetes, soil-dwelling bacteria of the genus Streptomyces. However, there is still a huge reservoir of streptomycetes NPs which remains pharmaceutically untapped and a compendium thereof could serve as a source of inspiration for the rational design of novel antibiotics. Initially released in 2012, StreptomeDB (http://www.pharmbioinf.uni-freiburg.de/streptomedb) is the first and only public online database that enables the interactive phylogenetic exploration of streptomycetes and their isolated or mutasynthesized NPs. In this third release, there are substantial improvements over its forerunners, especially in terms of data content. For instance, about 2500 unique NPs were newly annotated through manual curation of about 1300 PubMed-indexed articles, published in the last five years since the second release. To increase interoperability, StreptomeDB entries were hyperlinked to several spectral, (bio)chemical and chemical vendor databases, and also to a genome-based NP prediction server. Moreover, predicted pharmacokinetic and toxicity profiles were added. Lastly, some recent real-world use cases of StreptomeDB are highlighted, to illustrate its applicability in life sciences.

Cytochrome bd quinol:O2 oxidoreductases are respiratory terminal oxidases so far only identified in prokaryotes, including several pathogenic bacteria. Escherichia coli contains two bd oxidases of which only the bd-I type is structurally characterized. Here, we report the structure of the Escherichia coli cytochrome bd-II type oxidase with the bound inhibitor aurachin D as obtained by electron cryo-microscopy at 3 Å resolution. The oxidase consists of subunits AppB, C and X that show an architecture similar to that of bd-I. The three heme cofactors are found in AppC, while AppB is stabilized by a structural ubiquinone-8 at the homologous positions. A fourth subunit present in bd-I is lacking in bd-II. Accordingly, heme b595 is exposed to the membrane but heme d embedded within the protein and showing an unexpectedly high redox potential is the catalytically active centre. The structure of the Q-loop is fully resolved, revealing the specific aurachin binding.

Graphical abstract

In recent years, the drug discovery paradigm has shifted toward compounds that covalently modify disease-associated target proteins, because they tend to possess high potency, selectivity, and duration of action. The rational design of novel targeted covalent inhibitors (TCIs) typically starts from resolved macromolecular structures of target proteins in their apo or holo forms. However, the existing TCI databases contain only a paucity of covalent protein–ligand (cP–L) complexes. Herein, we report CovPDB, the first database solely dedicated to high-resolution cocrystal structures of biologically relevant cP–L complexes, curated from the Protein Data Bank. For these curated complexes, the chemical structures and warheads of pre-reactive electrophilic ligands as well as the covalent bonding mechanisms to their target proteins were expertly manually annotated. Totally, CovPDB contains 733 proteins and 1,501 ligands, relating to 2,294 cP–L complexes, 93 reactive warheads, 14 targetable residues, and 21 covalent mechanisms. Users are provided with an intuitive and interactive web interface that allows multiple search and browsing options to explore the covalent interactome at a molecular level in order to develop novel TCIs. CovPDB is freely accessible at http://www.pharmbioinf.uni-freiburg.de/covpdb/ and its contents are available for download as flat files of various formats.

Medicinal plants have widely been used in the traditional treatment of ailments and have been proven effective. Their contribution still holds an important place in modern drug discovery due to their chemical, and biological diversities. However, the poor documentation of traditional medicine, in developing African countries for instance, can lead to the loss of knowledge related to such practices. In this study, we present the Eastern Africa Natural Products Database (EANPDB) containing the structural and bioactivity information of 1870 unique molecules isolated from about 300 source species from the Eastern African region. This represents the largest collection of natural products (NPs) from this geographical region, covering literature data of the period from 1962 to 2019. The computed physicochemical properties and toxicity profiles of each compound have been included. A comparative analysis of some physico‐chemical properties like molecular weight, H‐bond donor/acceptor, logPo/w, etc. as well scaffold diversity analysis has been carried out with other published NP databases. EANPDB was combined with the previously published Northern African Natural Products Database (NANPDB), to form a merger African Natural Products Database (ANPDB), containing ∼6500 unique molecules isolated from about 1000 source species (freely available at http://african‐compounds.org). As a case study, latrunculins A and B isolated from the sponge Negombata magnifica (Podospongiidae) with previously reported antitumour activities, were identified via substructure searching as molecules to be explored as putative binders of histone deacetylases (HDACs).

Histone methylation reader proteins (HMRPs) regulate gene transcription by recognizing, at their “aromatic cage” domains, various Lys/Arg methylation states on histone tails. Because epigenetic dysregulation underlies a wide range of diseases, HMRPs have become attractive drug targets. However, structure-based efforts in targeting them are still in their infancy. Structural information from functionally unrelated aromatic-cage-containing proteins (ACCPs) and their cocrystallized ligands could be a good starting point. In this light, we mined the Protein Data Bank to retrieve the structures of ACCPs in complex with cationic peptidic/small-molecule ligands. Our analysis revealed that the vast majority of retrieved ACCPs belong to three classes: transcription regulators (chiefly HMRPs), signaling proteins, and hydrolases. Although acyclic (and monocyclic) amines and quats are the typical cation-binding functional groups found in HMRP small-molecule inhibitors, numerous atypical cationic groups were identified in non-HMRP inhibitors, which could serve as potential bioisosteres to methylated Lys/Arg on histone tails. Also, as HMRPs are involved in protein–protein interactions, they possess large binding sites, and thus, their selective inhibition might only be achieved by large and more flexible (beyond rule of five) ligands. Hence, the ligands of the collected dataset represent suitable versatile templates for further elaboration into potent and selective HMRP inhibitors.

Bioactive compounds oftentimes bind to several target proteins, thereby exhibiting polypharmacology. Experimentally determining these interactions is however laborious, and structure-based virtual screening (SBVS) of bioactive compounds could expedite drug discovery by prioritizing hits for experimental validation. Here, we present ePharmaLib, a library of 15,148 e-pharmacophores modeled from solved structures of pharmaceutically relevant protein−ligand complexes of the screening Protein Data Bank (sc-PDB). ePharmaLib can be used for target fishing of phenotypic hits, side effect predictions, drug repurposing, and scaffold hopping. In retrospective SBVS, a good balance was obtained between computational efficiency and predictive accuracy. As a proof of concept, we carried out prospective SBVS in conjunction with a photometric assay, which inferred that the mechanism of action of neopterin (an endogenous immunomodulator) putatively stems from its inhibition (IC 50 = 18 μM) of the human purine nucleoside phosphorylase. This ready-to-use library is freely available at http://www.pharmbioinf.uni-freiburg.de/epharmalib.