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

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

---

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(4), P. 824 - 838

Published: April 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.

Language: Английский

---

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

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(14), P. 6341 - 6349

Published: July 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.

Language: Английский

---

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

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(7), P. 104027 - 104027

Published: May 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.

Language: Английский

---

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

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: April 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.

Language: Английский

---

Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 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.

Language: Английский

---

Slow-binding inhibitors of enzymes: kinetic characteristics and pharmacological interest

Biomeditsinskaya Khimiya, Journal Year: 2025, Volume and Issue: 71(2), P. 81 - 94

Published: Jan. 1, 2025

Currently, the search for new slow-binding inhibitors of enzymes (SBI) and their identification primary in vitro studies still attracts much attention context potential role as putative pharmacological agents treatment various diseases. In contrast to classical reversible analogues, SBI exhibit a slow enzyme binding kinetics, where equilibrium steady-state is reached not microseconds, but after longer time intervals. Such compounds could be promising drugs, because regardless pharmacokinetics bloodstream, they have such advantages high affinity target enzyme, long residence on target, therefore, prolonged action. These properties ensure optimized dosage drugs required achieve activity with less side effects. this review we considered mechanisms interaction targets, principles recognition at level analysis kinetic parameters.

Language: Английский

---

Pantothenate kinase is an effective target for antifungal therapy

Cell chemical biology, Journal Year: 2025, Volume and Issue: 32(5), P. 710 - 721.e6

Published: May 1, 2025

Language: Английский

---

Overcoming Secondary Mutations of Type II Kinase Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(12), P. 9776 - 9788

Published: June 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.

Language: Английский

---

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

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 4, 2024

Language: Английский

---