This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.

/pdf/new-substructure-filters-for-removal-of-pan-assay-3e3dudtvn0.pdf

New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

We have previously reported on classes of compounds that can interfere with bioassays via a number of different mechanisms and termed such compounds Pan Assay INterference compoundS, or PAINS. These compounds were defined on the basis of high-throughput data derived from vendor-supplied synthetics. The question therefore arises whether the concept of PAINS is relevant to compounds of natural origin. Here, it is shown that this is indeed the case, but that the context of the biological readout is an important factor that must be brought into consideration.

Feeling Nature's PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS).

Anthraquinones (9,10-dioxoanthracenes) constitute an important class of natural and synthetic compounds with a wide range of applications. Besides their utilization as colorants, anthraquinone derivatives have been used since centuries for medical applications, for example, as laxatives and antimicrobial and antiinflammatory agents. Current therapeutic indications include constipation, arthritis, multiple sclerosis, and cancer. Moreover, biologically active anthraquinones derived from Reactive Blue 2 have been utilized as valuable tool compounds for biochemical and pharmacological studies. They may serve as lead structures for the development of future drugs. However, the presence of the quinone moiety in the structure of anthraquinones raises safety concerns, and anthraquinone laxatives have therefore been under critical reassessment. This review article provides an overview of the chemistry, biology, and toxicology of anthraquinones focusing on their application as drugs.

Anthraquinones As Pharmacological Tools and Drugs

Drug discovery considerations in the development of covalent inhibitors.

More than half a century ago, Linus Pauling wrote: “enzymes are molecules that are complementary in structure to the activated complexes of the reactions that they catalyze, ···, [rather than] entering into reactions.”1 This model has had a profound impact on drug design. Structure-based drug design usually involves the conceptualization and synthesis of molecules that have shapes and binding surfaces that are highly complementary to a protein receptor or enzyme binding site.2, 3 The goal is to achieve high binding affinity and selectivity. A drug must also have appropriate ADMET properties, but affinity is the first step.

Affinity and selectivity are generally improved by ensuring more perfect geometric and noncovalent interactions with a binding site. Crystal structures of a protein-ligand complex suggest structural modifications to better occupy a hydrophobic pocket. Such modifications can improve potency from the millimolar to the nanomolar range,4 and have helped lead to clinically approved compounds such as the HIV protease inhibitor nelfinavir.5, 6

Kuntz et al. have shown that small molecule affinity for protein binding sites resulting from noncovalent interactions generally peaks at 10 picomolar (10−11 M), corresponding to ΔGbinding of 15 kcal/mol.7 In contrast, binding constants for enzymes with transition states correspond to average Δ Gbinding of 22 kcal/mol, and up to 38 kcal/mol—many orders of magnitude stronger than can be attributed to noncovalent factors alone.8, 9 Earlier studies in our group have shown how these and other data point to the generality of covalent and partial covalent bonding in transition states of enzyme-catalyzed reactions.8, 9 This strength of binding may be achieved by fully covalent bonding such as Schiff base or acylenzyme intermediate formation, but partial covalent bonds that take place in general acid/base catalysis and interactions with metal cofactors can partially share electrons with the substrate or other reactants such as water molecules in the transition state.9

The harnessing of such strong covalent interactions could help provide the high potency that is needed at early stages of drug development. There has been a tendency to avoid covalent drugs, going back to studies in the early 1970s demonstrating hepatotoxicity as a result of covalent binding of compounds such as [14C]bromobenzene and acetaminophen.10, 11 At the same time, however, there are many examples of highly successful covalently acting drugs on the market, from proton pump inhibitors omeprazole and related compounds,12, 13 to the entire class of β-lactam antibiotics.14 The toxicity attributed to covalent binding is not an inherent feature of these interactions, per se, but rather a result of the specific spectrum of off-target modifications that may be made by the drug or even by metabolites of drugs whose primary mechanism of action is noncovalent.15, 16 Advances in chemical biology, along with bioinformatics data analysis methods, are increasingly able to unravel which covalent modifications are tolerable and which are toxic, suggesting a reevaluation of the role of covalent binding in drugs and drug leads.16–19 In this Perspective, the limits achievable by noncovalent binding in enzyme–inhibitor complexes, and the greater affinity achieved by covalent bonding of the drug to the receptor, are discussed. Selected examples of covalently acting drugs will be presented (for more comprehensive reviews see references 20, 21), as well as opportunities for their future structure-based design with advances in molecular modeling or screening with target-specific libraries.

/pdf/beyond-picomolar-affinities-quantitative-aspects-of-3sfo9f4kjg.pdf

Beyond picomolar affinities: quantitative aspects of noncovalent and covalent binding of drugs to proteins.

We have recently reported on the development of a La assay to detect reactive molecules by nuclear magnetic resonance (ALARM NMR) to detect reactive false positive hits from high-throughput screening, in which we observed a surprisingly large number of compounds that can oxidize or form covalent adducts with protein thiols groups. In the vast majority of these cases, the covalent interactions are largely nonspecific (e.g., affect many protein targets) and therefore unsuitable for drug development. However, certain thiol-reactive species do appear to inhibit the target of interest in a specific manner. The question then arises as to the potential toxicology risks of developing a drug that can react with protein thiol groups. Here, we report on the evaluation of a large set of ALARM-reactive and -nonreactive compounds against a panel of additional proteins (aldehyde dehydrogenase, superoxide dismutase, and three cytochrome P450 enzymes). It was observed that ALARM-reactive compounds have significantly increased risks of interacting with one or more of these enzymes in vitro. Thus, ALARM NMR seems to be a sensitive tool to rapidly identify compounds with an enhanced risk of producing side effects in humans, including alcohol intolerance, the formation of reactive oxygen species, and drug-drug interactions. In conjunction with other toxicology assays, ALARM NMR should be a valuable tool for prioritizing compounds for lead optimization and animal testing.

Toxicological evaluation of thiol-reactive compounds identified using a la assay to detect reactive molecules by nuclear magnetic resonance.

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Toxicological evaluation of thiol-reactive compounds identified using a la assay to detect reactive molecules by nuclear magnetic resonance.