The Heterogeneous Kinetic Origins of the Binding Properties of Orthosteric Ligands at Heteromeric Nicotinic Acetylcholine Receptors

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

A plethora of agonists and competitive antagonists have been developed to explore the therapeutic potential in neuronal nicotinic acetylcholine receptors (nAChRs). Based on equilibrium kinetic [3H]epibatidine binding studies, we report that fingerprints at five heteromeric αβ nAChRs seven classical α4β2 α3β4 differ substantially. While this diversity depends both agonist receptor subtype, overall pattern determinants emerging from profiling is complex. The dramatically different kinetics displayed by two alkaloids antagonists, (+)-DHβE (+)-cocculine, nAChR further exemplify how dissimilar can underlie very comparable pharmacological properties exhibited close structural analogs. Thus, our findings elucidate heterogeneous basis for orthosteric ligand emphasize affinities, selectivity profiles, structure-activity relationships these ligands are rooted their traits receptors.

Язык: Английский

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Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

ACS Chemical Biology, Год журнала: 2024, Номер 19(4), С. 824 - 838

Опубликована: Апрель 3, 2024

Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading covalent adducts, there been success developing inhibitors, especially within field anticancer therapy. inhibitors can have an advantage over noncovalent since formation adduct may serve as additional mode selectivity intrinsic reactivity target protein that is absent many other proteins. Unfortunately, form irreversible adducts with proteins, which lead considerable side-effects. By designing inhibitor reversible one leverage competing on/off kinetics complex taking law mass action. do nature prevents accumulation adduct, thus limiting In this perspective, we outline important characteristics including examples and guide for development.

Язык: Английский

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Calculating Protein–Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер 20(14), С. 6341 - 6349

Опубликована: Июль 11, 2024

Understanding drug residence times in target proteins is key to improving efficacy and understanding recognition biochemistry. While time just as important binding affinity, atomic-level of through molecular dynamics (MD) simulations has been difficult primarily due the extremely long scales. Recent advances rare event sampling have allowed us reach these scales, yet predicting protein-ligand remains a significant challenge. Here we present semi-automated protocol calculate ligand across 12 orders magnitude In our proposed framework, integrate deep learning-based method, state predictive information bottleneck (SPIB), learn an approximate reaction coordinate (RC) use it guide enhanced method metadynamics. We demonstrate performance algorithm by applying six different complexes with available benchmark times, including dissociation widely studied anticancer Imatinib (Gleevec) from both wild-type Abl kinase drug-resistant mutants. show how can recover quantitatively accurate potentially opening avenues for deeper insights into development possibilities mechanisms.

Язык: Английский

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Coupling of surface plasmon resonance and mass spectrometry for molecular interaction studies in drug discovery

Drug Discovery Today, Год журнала: 2024, Номер 29(7), С. 104027 - 104027

Опубликована: Май 17, 2024

Various analytical technologies have been developed for the study of target-ligand interactions. The combination these gives pivotal information on binding mechanism, kinetics, affinity, residence time, and changes in molecular structures. Mass spectrometry (MS) offers structural information, enabling identification quantification Surface plasmon resonance (SPR) provides kinetic interaction real time. coupling MS SPR complements each other studies Over last two decades, capabilities added values SPR-MS reported. This review summarizes highlights benefits, applications, potential further research approach.

Язык: Английский

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Time‐evolved metrics for safety pharmacological assessments of small molecules and biologics

British Journal of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 27, 2025

Abstract Safety of a small‐molecule drug is oftentimes more important criterion than efficacy in determining approval. Aspects safety pharmacological and toxicological liabilities, often resulting from dose‐dependent undesirable interaction with either the primary target interest or secondary targets, have huge role to play ‘first‐in‐human’ dosage phase I clinical trials. Given open thermodynamic nature human subjects, it mandatory that kinetics drug‐target drug‐off‐target interactions govern way selectivity margins are assessed, dose decided. However, lack sufficient thrust on guiding early discovery decisions has resulted an overreliance IC 50 measure (a proxy for K i ) as means computing across potential off‐targets. Moreover, based established practises known weight evidence targets adverse events, panel pharmacology biased greater preference G‐protein coupled receptors, transporters ion‐channels paucity enzymes. This can pose unique challenges assessing safety, especially advancing emergent modalities. In this perspective, critical kinetic should emphasised given myriad assay conditions modulate equilibrium embodied report . Further, advocates selective judicious expansion panels representation enzymes reduced redundancy eventual read‐outs correlative output among off‐target classes assessed.

Язык: Английский

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Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 29, 2025

DHX9 is an RNA/DNA helicase integral in the maintenance of genome stability that has emerged as attractive target for oncology drug discovery. Disclosed herein discovery and optimization a series inhibitors. Compound 1 was identified partial inhibitor ATPase activity but full unwinding activity. Binding to pocket distinct from ATP binding site confirmed by X-ray crystallography, enabling structure-based optimization. During this optimization, sulfur-halogen bond increased on-target residence time without impacting equilibrium affinity. Analysis shows cell potency more closely correlates with than measurements affinity or biochemical potency. Further ADME properties led identification ATX968, potent selective efficacious tumor xenograft model microsatellite instability-high (MSI-H) colorectal cancer.

Язык: Английский

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Pantothenate kinase is an effective target for antifungal therapy

Cell chemical biology, Год журнала: 2025, Номер 32(5), С. 710 - 721.e6

Опубликована: Май 1, 2025

Язык: Английский

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Overcoming Secondary Mutations of Type II Kinase Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(12), С. 9776 - 9788

Опубликована: Июнь 5, 2024

Type II kinase inhibitors bind in the "DFG-out" conformation and are generally considered to be more potent selective than type I inhibitors, which target a DFG-in conformation. Nine currently clinically approved, with undergoing clinical development. Resistance-conferring secondary mutations emerged first series of most commonly at residues within activation loop "gatekeeper" position. Recently, new have been developed overcome such mutations; however, activating other pathways (and/or targets) subsequently on occasion. Here, we systematically summarize that confer resistance structural basis for resistance, newer designed as well challenges opportunities development domain mutations.

Язык: Английский

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Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 4, 2024

Язык: Английский

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Breath and Beyond: Advances in Nanomedicine for Oral and Intranasal Aerosol Drug Delivery

Pharmaceuticals, Год журнала: 2024, Номер 17(12), С. 1742 - 1742

Опубликована: Дек. 23, 2024

Designing and standardizing drug formulations are crucial for ensuring the safety efficacy of medications. Nanomedicine utilizes nano delivery systems advanced nanodevices to address numerous critical medical challenges. Currently, oral intranasal aerosol (OIADD) is primary method treating respiratory diseases worldwide. With advancements in disease understanding development aerosolized systems, application OIADD has exceeded its traditional boundaries, demonstrating significant potential treatment non-respiratory conditions as well. This study provides a comprehensive overview applications treatment. It examines key challenges limiting nanomedicines formulation processes, devices explores latest these areas. review aims offer valuable insights researchers involved platforms.

Язык: Английский

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