Molecular dynamics simulation of the inhibition mechanism of factor XIa by Milvexian-like macrocyclic inhibitors

Zhang, Hao; Guan, Shanshan; Du, Juan; Zhang, Yurou; Wang, Song

doi:10.1016/j.comptc.2023.114131

Cited by 7 publications

(2 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The molecular dynamics (MD) simulation was performed using the Desmond module of Schrodinger suite 2021-1 with Linux (Ubuntu, 23.10) equipped with an NVIDIA Quadro K2200 graphics card. A simulation period of 100 ns was employed to investigate the thermodynamic stability of KS82 and KS94 complexed with viral proteins [ 38 , 39 , 40 ]. The ligand–protein complex was built with the explicit solvent system (TIP3P) and centered with an orthorhombic periodic boundary box.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2

Sharma,

Singh,

Sharma

et al. 2024

Molecules

View full text Add to dashboard Cite

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The Mpro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of β-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 MPro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties.

show abstract

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2

Sharma,

Singh,

Sharma

et al. 2024

Molecules

View full text Add to dashboard Cite

show abstract

“…By conducting a molecular dynamics (MD) simulation over an interval of 100 ns employing the molecular dynamics component of Schrodinger's Desmond software 2023-2, the proposed analogues with favourable linking energy levels in comparison to the GSK 3β enzyme were additionally evaluated for their thermal equilibrium with reference to time [28][29][30][31]. By achieving the compound's most desired configuration following interactions in relation to duration, the lowered or minimised energy simulations helped strengthen the protein-ligand interaction.…”

Section: Molecular Dynamic Simulationsmentioning

confidence: 99%

In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3β (GSK-3β)

Goyal,

Singh,

Thirumal

et al. 2023

Biomedicines

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid-beta (Aβ) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has a propensity for microtubules, which elevate the instability and tau-protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK-3, which has led to an emerging hypothesis regarding the pathogenesis of AD. Accordingly, attempts have been made to conduct investigations and achieve further advancements on new analogues capable of inhibiting the GSK-3 protein, which are currently in the clinical trials. In this analysis, we have evaluated certain GSK-3 inhibitor variants utilising scaffolding and framework devised techniques with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking). The structure-based designed analogues interacted effectively with the active amino acids of GSK-3β target protein. The in silico pharmacokinetic studies revealed their drug-like properties. The analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK-3 inhibitors.

show abstract

Harnessing computational and experimental approaches to identify potent hits against Leishmania donovani sterol C-24 methyltransferase from ChemBridge library

Kumari,

Palmo,

Mujwar

et al. 2024

Acta Tropica

View full text Add to dashboard Cite

Molecular dynamics simulation of the inhibition mechanism of factor XIa by Milvexian-like macrocyclic inhibitors

Cited by 7 publications

References 74 publications

Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2

Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2

In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3β (GSK-3β)

Harnessing computational and experimental approaches to identify potent hits against Leishmania donovani sterol C-24 methyltransferase from ChemBridge library

Contact Info

Product

Resources

About