scholarly journals Molecular modeling of mechanism of action of anti-myasthenia gravis slow-binding inhibitor of acetylcholinesterase

2015 ◽  
Vol 27 (s1) ◽  
pp. S74-S75
Author(s):  
S. Lushchekina ◽  
E. Kots ◽  
A. Kharlamova ◽  
K. Petrov ◽  
P. Masson
Keyword(s):  
Molecular Modeling ◽  
Myasthenia Gravis ◽  
Mechanism Of Action ◽  
Slow Binding Inhibitor

Structural differences between HLA-DQ molecules associated with myasthenia gravis characterized by molecular modeling

1998 ◽  
Vol 85 (1) ◽  
pp. 102-105 ◽  
Author(s):  
P Hjelmström ◽  
C DeWeese-Scott ◽  
J.E Penzotti ◽  
T.P Lybrand ◽  
C.B Sanjeevi
Keyword(s):  
Molecular Modeling ◽  
Myasthenia Gravis ◽  
Hla Dq ◽  
Structural Differences

Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment

2016 ◽  
Vol 473 (9) ◽  
pp. 1225-1236 ◽  
Author(s):  
Alexandra D. Kharlamova ◽  
Sofya V. Lushchekina ◽  
Konstantin A. Petrov ◽  
Ekaterina D. Kots ◽  
Florian Nachon ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Myasthenia Gravis ◽  
Slow Step ◽  
Type B ◽  
Reversible Inhibitors ◽  
Compound C ◽  
Hydrogen Bonding Interactions ◽  
Binding Inhibition ◽  
Dynamics Simulations ◽  
Slow Binding Inhibitor

Inhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative of 6-methyluracil, C-547, a potential drug for the treatment of MG (myasthenia gravis) was studied. Kinetic analysis of AChE inhibition showed that C-547 is a slow-binding inhibitor of type B, i.e. after formation of the initial enzyme·inhibitor complex (Ki=140 pM), an induced-fit step allows establishment of the final complex (Ki*=22 pM). The estimated koff is low, 0.05 min−1. On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki=1.77 μM; Ki′=3.17 μM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 Å resolution. The complex is stabilized by cation–π, stacking and hydrogen-bonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a non-charged analogue) to mouse and human AChEs were performed. Molecular modelling on mouse and human AChE showed that the slow step results from an enzyme conformational change that allows C-547 to cross the bottleneck in the active-site gorge, followed by formation of tight complex, as observed in the crystal structure. In contrast, the related non-charged compound C-35 is not a slow-binding inhibitor. It does not cross the bottleneck because it is not sensitive to the electrostatic driving force to reach the bottom of the gorge. Thus C-547 is one of the most potent and selective reversible inhibitors of AChE with a long residence time, τ=20 min, longer than for other reversible inhibitors used in the treatment of MG. This makes C-547 a promising drug for the treatment of this disease.

scholarly journals Molecular modeling and UV–vis spectroscopic studies on the mechanism of action of reversed chloroquine (RCQ)

2011 ◽  
Vol 21 (1) ◽  
pp. 250-254 ◽  
Author(s):  
Vanessa A. Otelo ◽  
Antonio C. Sant’Ana ◽  
Dalva L.A. de Faria ◽  
Carla M.S. Menezes
Keyword(s):  
Molecular Modeling ◽  
Mechanism Of Action ◽  
Spectroscopic Studies

scholarly journals Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-β-Carbolines

2021 ◽  
Vol 22 (24) ◽  
pp. 13569
Author(s):  
Anna Jaromin ◽  
Beata Gryzło ◽  
Marek Jamrozik ◽  
Silvia Parapini ◽  
Nicoletta Basilico ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
Mechanism Of Action ◽  
Blood Cells ◽  
Antiplasmodial Activity ◽  
Drug Resistant ◽  
Human Red Blood Cells ◽  
Molecular Modeling Studies

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet–Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

scholarly journals Molecular modeling and mechanism of action of human decay-accelerating factor

1996 ◽  
Vol 9 (12) ◽  
pp. 1143-1149 ◽  
Author(s):  
Lisa Kuttner-Kondo ◽  
M.Edward Medof ◽  
William Brodbeck ◽  
Menachem Shoham
Keyword(s):  
Molecular Modeling ◽  
Mechanism Of Action ◽  
Decay Accelerating Factor

scholarly journals Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII

2019 ◽  
Vol 20 (5) ◽  
pp. 1208 ◽  
Author(s):  
Kerem Buran ◽  
Silvia Bua ◽  
Giulio Poli ◽  
F. Önen Bayram ◽  
Tiziano Tuccinardi ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Carbonic Anhydrase ◽  
Mechanism Of Action ◽  
Inhibitory Activity ◽  
Carbonic Anhydrase Ix ◽  
Specific Mechanism ◽  
Single Digit ◽  
Molecular Modeling Studies ◽  
Human Carbonic Anhydrase ◽  
Substituted Coumarins

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.

Sign in / Sign up

Export Citation Format

Share Document