Application of the Linear Interaction Energy Method to Nitric Oxide Synthase Structure-Based Inhibitor Design DOI
Alec H. Follmer, T.L. Poulos

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(22), P. 8586 - 8594

Published: Nov. 7, 2024

The overproduction of nitric oxide by neuronal synthase (nNOS) is associated with several neuropathological conditions. As a result, inhibition nNOS desirable therapeutic goal while avoiding the endothelial NOS (eNOS) given its essential role in maintaining cardiovascular tone. Designing inhibitors high specificity for over eNOS challenging close similarity active site structure all mammalian isoforms. Computational methods like free energy perturbation (FEP) and thermodynamic integration (TI) offer attractive avenues rational drug design, but application these to hindered challenges, including proper handling highly charged diverse structures as well computational expense. To address issues, we present simplified approach combining continuum dielectric generalized born (GB) solvent models linear interaction (LIE) calculations. Our method demonstrates excellent agreement experimental data targeting isoforms (mNOS). results highlight utility GB-LIE promising tool screening potentially other protein targets sites inhibitor structures.

Language: Английский

Discovery of novel theophylline derivatives bearing tetrazole scaffold for the treatment of Alzheimer's disease DOI Creative Commons
Nguyễn Viết Hưng,

Le Quoc Tien,

Linh Hoang Vu

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(9), P. 6994 - 7003

Published: Jan. 1, 2025

Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of BACE1. particular, potential inhibitory compounds was rapidly accurately estimated via knowledge-methods. The in vitro tests then performed validate artificial intelligent approach. Among these, compound 12 exhibited most potent inhibition an IC50 15.68 μM, while showing limited against addition, six indicated that are able inhibit AChE, however, play poor performance over target. Atomistic simulations finally applied clarify ligand-binding mechanism outcomes disclose rigidly form van der Waals interactions π-stacking SC contacts. Overall, may offer a scaffold novel anti-AD agents.

Language: Английский

Citations

0
Discovery of Novel DDR1 Inhibitors through a Hybrid Virtual Screening Pipeline, Biological Evaluation and Molecular Dynamics Simulations DOI Creative Commons

Xinglong Chi,

Roufen Chen,

Xinle Yang

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(4), P. 602 - 610

Published: March 17, 2025

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy with limited therapeutic options for many patients. Discoidin domain receptor 1 (DDR1), transmembrane tyrosine kinase receptor, has been implicated in AML progression and represents promising target. In this study, we employed hybrid virtual screening workflow that integrates deep learning-based binding affinity predictions molecular docking techniques to identify potential DDR1 inhibitors. A multistage process involving PSICHIC, KarmaDock, Vina-GPU, similarity-based scoring was conducted, leading the selection of seven candidate compounds. The biological evaluation identified Compound 4 as novel inhibitor, demonstrating significant inhibitory activity an IC50 46.16 nM 99.86% inhibition rate against Z-138 cells at 10 μM. Molecular dynamics simulations free energy calculations further validated stability strong interactions DDR1. This study highlights utility combining learning models traditional accelerate discovery potent selective compounds hold promise development targeted therapies AML.

Language: Английский

Citations

0
Tripeptides inhibit dual targets AChE and BACE-1: a computational study DOI Creative Commons

Anh Tuan,

Trung Hai Nguyen, Phạm Minh Quân

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(16), P. 12866 - 12875

Published: Jan. 1, 2025

Computational identification of tripeptides as promising dual AChE/BACE-1 inhibitors for Alzheimer's therapy.

Language: Английский

Citations

0
Insights into the inhibitory activity and mechanism of natural compounds from Rhinacanthus nasutus on α-glucosidase through kinetic, molecular docking, and molecular dynamics studies DOI
Thi‐Kim‐Dung Le,

Felicitas Ene,

Thuc‐Huy Duong

et al.

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: unknown, P. 140527 - 140527

Published: Oct. 1, 2024

Language: Английский

Citations

1
Application of the Linear Interaction Energy Method to Nitric Oxide Synthase Structure-Based Inhibitor Design DOI
Alec H. Follmer, T.L. Poulos

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(22), P. 8586 - 8594

Published: Nov. 7, 2024

The overproduction of nitric oxide by neuronal synthase (nNOS) is associated with several neuropathological conditions. As a result, inhibition nNOS desirable therapeutic goal while avoiding the endothelial NOS (eNOS) given its essential role in maintaining cardiovascular tone. Designing inhibitors high specificity for over eNOS challenging close similarity active site structure all mammalian isoforms. Computational methods like free energy perturbation (FEP) and thermodynamic integration (TI) offer attractive avenues rational drug design, but application these to hindered challenges, including proper handling highly charged diverse structures as well computational expense. To address issues, we present simplified approach combining continuum dielectric generalized born (GB) solvent models linear interaction (LIE) calculations. Our method demonstrates excellent agreement experimental data targeting isoforms (mNOS). results highlight utility GB-LIE promising tool screening potentially other protein targets sites inhibitor structures.

Language: Английский

Citations

1