Advances in protein chemistry and structural biology, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 1, 2024
Language: Английский
Molecules, Journal Year: 2025, Volume and Issue: 30(4), P. 805 - 805
Published: Feb. 10, 2025
The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in virus's life cycle and plays a pivotal role COVID-19. Understanding how small molecules inhibit 3CLpro's activity vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance sampling 3CLpro conformations conducted correlation network analysis (CNA) explore interactions between different structural domains. Our findings indicate that CNA-identified node domain II acts conduit, transferring conformational changes from catalytic regions domains I II, triggered by binding inhibitors (7YY, 7XB, Y6G), III, thereby modulating activity. Normal mode (NMA) principal component (PCA) revealed inhibitor affects flexibility collective movements sites influencing function. free energies, predicted both MM-GBSA QM/MM-GBSA methods, showed high with experimental data, validating reliability our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, E166, identified through residue-based energy decomposition, present promising targets design drugs could facilitate development clinically effective inhibitors.
Language: Английский
Citations
4
Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown
Published: March 16, 2025
Language: Английский
Citations
0
Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown
Published: April 8, 2025
The activity of the enzyme JAK3 is modulated by tyrosine phosphorylation, yet underlying molecular details remain not fully understood. In this study, we employed a GaMD trajectory-based Markov model and correlation network analysis (CNA) to investigate impact single phosphorylation (SP) at Y980 (pY980) double (DP) Y980/Y981 (pY980/pY981) on conformational dynamics bound inhibitors IZA MI1. indicated that both SP DP result in fewer states significantly influence P-loop, αC-helix, loop1-loop3, while maintaining hinge region's high rigidity. CNA findings revealed alters communication among different structural regions JAK3, providing rational explanation for how affects distant P-loop loop1-loop3. Moreover, changes mediated further affect interactions between hot spots (L828, V836, E903, Y904, L905, L956) JAK3. This work offers valuable theoretical insights into mechanisms regulate activity.
Language: Английский
Citations
0
Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(42), P. 26784 - 26798
Published: Jan. 1, 2024
In 2020, cancer-related deaths reached 9.96 million globally, of which China accounted for 3 million, ranking first in the world. Phosphoglycerate mutase 1 (PGAM1) is a key metabolic enzyme glycolysis, catalysing conversion 3-phosphoglycerate to 2-phosphoglycerate. Based on excellent anticancer activity PGMI-004A and HKB99, new small molecules with an anthraquinone core were synthesised inhibit tumour growth. Developing targeting PGAM1 may be effective strategy treating cancer. this study, accelerated molecular dynamics (aMD) simulation, dynamic cross-correlation map (DCCM) calculation, principal component analysis (PCA) free energy landscape (FEL) used analyse conformational changes caused by binding inhibitors 8KX, 9HU HKB. DCCM calculations PCA showed that inhibitor significantly affected kinetic behaviour rearrangement PGAM1. The ability mechanism HKB studied using mechanics generalised Born surface area (MM-GBSA) method. results compared was enhanced sulphonamide reversal aminocarboxyl trifluoromethyl substitution. There several hydrophobic interactions between PGAM1, providing significant contributions binding. Calculation residue-based decomposition revealed F22, R90, Y92, L95, V112, W115, R116, V121, P123, P124, R191 M206 residues PGAM1-inhibitor interaction could as targets designing drugs
Language: Английский
Citations
2
Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(20), P. 7998 - 8009
Published: Oct. 10, 2024
Under the selective pressure of nirmatrelvir, a peptidomimetic covalent drug targeting SARS-CoV-2 Mpro, various drug-resistant mutations on Mpro have been acquired in vitro. Among mutations, L50F and E166V, along with combination are particularly representative pose considerable obstacles to effective treatment COVID-19. Our previous study identified NMI-001 NMI-002 as novel nonpeptide inhibitors that target possessing unique scaffolds binding modes different from those nirmatrelvir. In view these findings, we proposed design strategy aimed at rapidly identifying can combat mutation-induced resistance. Initially, molecular dynamics (MD) simulation was employed investigate mechanisms against three mutants (Mpro_L50F, Mpro_E166V, Mpro_L50F+E166V). Then, conducted two phases high-throughput virtual screening. first phase, served template perform scaffold hopping-based similarity search library 15,742,661 compounds. second 968 compounds exhibiting were evaluated via docking MD simulations. Six may be least one mutant identified, five procured for conducting vitro assays. Finally, compound Z1557501297 (NMI-003) inhibitory effects E166V (IC50 = 27.81 ± 2.65 μM) L50F+E166V 8.78 0.74 discovered. The referring NMI-003-Mpro_E166V NMI-003-Mpro_L50F+E166V further elucidated atomic level. summary, NMI-003 reported herein is activity L50F+E166V, which provides good starting point antiviral drugs SARS-CoV-2.
Language: Английский
Citations
2
Advances in protein chemistry and structural biology, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 1, 2024
Language: Английский
Citations
0
Advances in protein chemistry and structural biology, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 1, 2024
Language: Английский
Citations
0