Molecular profiling efforts aim at characterizing the biological actions of small molecules by screening them in hundreds of different biochemical and/or cell-based assays. Together, these assays ...yield a rich data landscape of target-based and phenotypic effects of the tested compounds. However, submitting an entire compound library to a molecular profiling panel can easily become cost-prohibitive. Here, we make use of historical screening assays to create comprehensive bioactivity profiles for more than 300 000 small molecules. These bioactivity profiles, termed PubChem high-throughput screening fingerprints (PubChem HTSFPs), report small molecule activities in 243 different PubChem bioassays. Although the assays originate from originally independently pursued drug or probe discovery projects, we demonstrate their value as molecular signatures when used in combination. We use these PubChem HTSFPs as molecular descriptors in hit expansion experiments for 33 different targets and phenotypes, showing that, on average, they lead to 27 times as many hits in a set of 1000 chosen molecules as a random screening subset of the same size (average ROC score: 0.82). Moreover, we demonstrate that PubChem HTSFPs retrieve hits that are structurally diverse and distinct from active compounds retrieved by chemical similarity-based hit expansion methods. PubChem HTSFPs are made freely available for the chemical biology research community.
The association between molecular size and risk of failure has promoted the use of binding efficiency as a prioritization metric in lead selection. Even though by extension it is often referred to as ...“ligand efficiency”, the concept was originally conceived to be strictly applicable to comparing the binding efficiencies of ligands for a single target. With current trends in designing drugs to bind efficiently to multiple targets, a revision of the original binding efficiency definition is carried out. To this aim, the dependency of binding efficiency on polypharmacology is highlighted in a retrospective analysis of a set of antipsychotic drugs. Statistical standardization of target binding efficiencies relative to basal values obtained from a large background of medicinal chemistry compounds is proposed as a means to conciliate the concepts of binding efficiency and polypharmacology. Finally, the interplay between binding efficiency and therapeutic efficacy for optimizing natural products, random hits, and fragments is discussed.
A novel set of molecular descriptors called SHED (SHannon Entropy Descriptors) is presented. They are derived from distributions of atom-centered feature pairs extracted directly from the topology of ...molecules. The value of a SHED is then obtained by applying the information-theoretical concept of Shannon entropy to quantify the variability in a feature-pair distribution. The collection of SHED values reflecting the overall distribution of pharmacophoric features in a molecule constitutes its SHED profile. Similarity between pairs of molecules is then assessed by calculating the Euclidean distance of their SHED profiles. Under the assumption that molecules having similar pharmacological profiles should contain similar features distributed in a similar manner, examples are given to show the ability of SHED for scaffold hopping in virtual chemical screening and pharmacological profiling compared to that of substructural BCI fingerprints and three-dimensional GRIND descriptors.
Aberrant activation of signaling pathways plays a pivotal role in central nervous system disorders, such as Alzheimer's disease (AD). Using a combination of virtual screening and experimental ...testing, novel small molecule inhibitors of tPA-mediated extracellular signal-regulated kinase (Erk)1/2 activation were identified that provide higher levels of neuroprotection from Aβ-induced apoptosis than Memantine, the most recently FDA-approved drug for AD treatment. Subsequent target deconvolution efforts revealed that they all share low micromolar affinity for the imidazoline I2 receptor, while being devoid of any significant affinity to a list of AD-relevant targets, including the N-methyl-d-aspartate receptor (NMDAR), acetylcholinesterase (AChE), and monoamine oxidase B (MAO-B). Targeting the imidazoline I2 receptor emerges as a new mechanism of action to inhibit tPA-induced signaling in neurons for the treatment of AD and other neurodegenerative diseases.
The design of chemical libraries directed to target classes is an activity that requires the availability of ligand pharmacological data and/or protein structural data. On the basis of the knowledge ...derived from these data, chemical libraries directed mainly to G protein-coupled receptors, kinases, proteases, and nuclear receptors have been assembled. However, current design strategies widely overlook assessing the potential ability of the compounds contained in a focused library to provide uniform ample coverage of the protein family they intend to target. Here, we discuss the use of
in silico target profiling methods as a means to estimate the actual scope of chemical libraries to probe entire protein families and illustrate its applicability in optimizing the composition of compound sets to achieve maximum coverage of the family with minimum bias to particular targets.
Bioactive ligands are a valuable and increasingly accessible source of information about protein targets. On the basis of this statement, a list of 25 nuclear receptors was described by a series of ...bioactive ligands extracted directly from bibliographical sources, stored properly in an annotated chemical library, and mathematically represented using the recently reported SHED molecular descriptors. Analysis of this ligand information allowed for derivation of a threshold of nuclear receptor concern. If the similarity of one molecule to any of the molecules annotated to one particular nuclear receptor is below that threshold, the molecule receives an alert on the probability of having affinity below 10 μM for that nuclear receptor. On this basis, a linkage map was constructed that reveals the interaction network of nuclear receptors from the perspective of their active ligands. This ligand-based approach to nuclear receptor profiling was subsequently applied to four external chemical libraries of 10 000 molecules targeted to proteases, kinases, ion channels, and G protein-coupled receptors. The percentage of each library that returned an alert on at least one nuclear receptor was reasonably low and varied between 4.4 and 9.7%. In addition, ligand-based nuclear receptor profiling of a set of 2944 drugs provided an alert for 153 drugs. For some of them, namely, acitretin, telmisartan, phenyltoloxamine, tazarotene, and flumazenil, bibliographical evidence could be found indicating that those drugs may indeed have some potential off-target residual affinity for the nuclear receptors annotated. Overall, the present findings suggest that ligand-based approaches to protein family profiling appear as a promising means toward the establishment of novel tools for in silico pharmacology.
Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a ...chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest.
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