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Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

ABSTRACT: Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic applications that could benefit from this type of data mining is proteasome inhibition, given that multiple compounds have been designed and tested for the last 20 years, and this collection of data is yet to be subjected to such type of assessment. This study presents a retrospective overview of two decades of proteasome inhibitors development (680 compounds), in order to gather what could be learned from them and apply this knowledge to any future drug discovery on this subject. Our analysis focused on how different chemical descriptors coupled with statistical tools can be used to extract interesting patterns of activity. Multiple instances of the structure-activity relationship were observed in this dataset, either for isolated molecular descriptors (e.g., molecular refractivity and topological polar surface area) as well as scaffold similarity or chemical space overlap. Building a decision tree allowed the identification of two meaningful decision rules that describe the chemical parameters associated with high activity. Additionally, a characterization of the prevalence of key functional groups gives insight into global patterns followed in drug discovery projects, and highlights some systematically underexplored parts of the chemical space. The various chemical patterns identified provided useful insight that can be applied in future drug discovery projects, and give an overview of what has been done so far.

SUBMITTER: Guedes RA

PROVIDER: S-EPMC6862029 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

Guedes Romina A RA Aniceto Natália N Andrade Marina A P MAP Salvador Jorge A R JAR Guedes Rita C RC

International journal of molecular sciences 20191025 21

Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic app ...[more]

PMID: 31731563

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Project description:Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity.

Project description:BackgroundHistone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells.ResultsA panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition.ConclusionsHigh-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.

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Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

Publications

Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

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