Comparative QM/MM Molecular Dynamics and Umbrella Sampling Simulations: Interaction of the Zinc-Bound Intermediate Gem-Diolate Trapoxin A Inhibitor and Acetyl-l-lysine Substrate with Histone Deacetylase 8

2021 ◽  
Author(s):  
Waleed A. Zalloum ◽  
Needa Zalloum
Keyword(s):  
Molecular Dynamics ◽  
Histone Deacetylase ◽  
Umbrella Sampling ◽  
Histone Deacetylase 8

scholarly journals Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1051
Author(s):  
Edgardo Becerra ◽  
Giovanny Aguilera-Durán ◽  
Laura Berumen ◽  
Antonio Romo-Mancillas ◽  
Guadalupe García-Alcocer
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Binding Site ◽  
Binding Sites ◽  
Adenosine Monophosphate ◽  
Competitive Inhibitor ◽  
Umbrella Sampling ◽  
Coarse Grained ◽  
Nucleotide Polymorphisms

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.

Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries

2012 ◽  
Vol 55 (22) ◽  
pp. 9562-9575 ◽  
Author(s):  
Takayoshi Suzuki ◽  
Yosuke Ota ◽  
Masaki Ri ◽  
Masashige Bando ◽  
Aogu Gotoh ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Histone Deacetylase ◽  
Selective Inhibitors ◽  
Histone Deacetylase 8

scholarly journals The inhibition of histone deacetylase 8 suppresses proliferation and inhibits apoptosis in gastric adenocarcinoma

2015 ◽  
Vol 47 (5) ◽  
pp. 1819-1828 ◽  
Author(s):  
SHIYUAN SONG ◽  
YING WANG ◽  
PO XU ◽  
RUINA YANG ◽  
ZHIKUN MA ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Gastric Adenocarcinoma ◽  
Histone Deacetylase 8
Sign in / Sign up

Export Citation Format

Share Document