scholarly journals Druggability analysis of membrane proteins by DoGSiteScorer

2017 ◽  
Author(s):  
Ning Zhang ◽  
Daiwei Li
Keyword(s):  
Crystal Structure ◽  
Membrane Proteins ◽  
Virus Entry ◽  
P2y12 Receptor ◽  
Ligand Complex ◽  
Cardiac Muscle Cells ◽  
Receptor Ligand ◽  
Binding Pockets ◽  
Hiv 1 ◽  
Grid Based

Membrane proteins are the most medicinally important yet to be fully exploited pharmaceutical targets. Here druggability analyses are conducted on three different membrane proteins, namely, the human P2Y12 receptor, glycoprotein-41 that mediates the HIV-1 virus entry and membrane fusion, and phospholamban that regulates the Ca2+ pump in cardiac muscle cells. DoGSiteScorer, a grid-based bioinfromatic technology, is able to identify the binding pockets of all three membrane proteins, and the results were in great agreements with the available crystal structure of P2Y12 receptor-ligand complex. This druggability analysis is especially helpful in cases where the crystal structures of membrane protein-ligand complexes are still difficult to obtain. Better understanding of the druggable pockets of membrane proteins also requires including the membrane environment.

scholarly journals Druggability analysis of membrane proteins by DoGSiteScorer

2017 ◽  
Author(s):  
Ning Zhang ◽  
Daiwei Li
Keyword(s):  
Crystal Structure ◽  
Membrane Proteins ◽  
Virus Entry ◽  
P2y12 Receptor ◽  
Ligand Complex ◽  
Cardiac Muscle Cells ◽  
Receptor Ligand ◽  
Binding Pockets ◽  
Hiv 1 ◽  
Grid Based

Membrane proteins are the most medicinally important yet to be fully exploited pharmaceutical targets. Here druggability analyses are conducted on three different membrane proteins, namely, the human P2Y12 receptor, glycoprotein-41 that mediates the HIV-1 virus entry and membrane fusion, and phospholamban that regulates the Ca2+ pump in cardiac muscle cells. DoGSiteScorer, a grid-based bioinfromatic technology, is able to identify the binding pockets of all three membrane proteins, and the results were in great agreements with the available crystal structure of P2Y12 receptor-ligand complex. This druggability analysis is especially helpful in cases where the crystal structures of membrane protein-ligand complexes are still difficult to obtain. Better understanding of the druggable pockets of membrane proteins also requires including the membrane environment.

Preparation of Target CETP in Docking-Based Virtual Screening

2013 ◽  
Vol 477-478 ◽  
pp. 1495-1498
Author(s):  
Wei Ye Tao ◽  
Lai You Wang ◽  
Guo Quan Huang ◽  
Man Luo
Keyword(s):  
Crystal Structure ◽  
Virtual Screening ◽  
Cholesteryl Ester ◽  
Active Site ◽  
Target Protein ◽  
Drug Molecule ◽  
Ligand Complex ◽  
Receptor Ligand ◽  
Strong Repulsion

When conducting docking-based virtual screening, we should carefully prepare the target protein. Generally, the ligands coupled with the receptor-ligand complex are often deleted from the crystal structure, but it is unknown that in which situation the ligands should be deleted. Taking CETP for example, this study conducted virtual screening against CETP through 2 different styles. In style 1, the cholesteryl ester near the active site was deleted. In style 2, the cholesteryl ester was kept to conduct the virtual screening. We found that the results were very different from each other and style 2 was the preferable choice in this situation. The reason why like this is that there is strong repulsion between drug molecule and the cholesteryl ester.

A Novel Synthetic Chemokine Containing D-Amino Acids That Binds to the CXCR4 Receptor and Inhibits HIV-1 Infection.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 603-603
Author(s):  
Ziwei Huang ◽  
Dongxiang Liu ◽  
Navid Madani ◽  
Santosh Kumar ◽  
Won-Tak Choi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Binding Affinity ◽  
Chemokine Receptors ◽  
Structural Changes ◽  
Virus Entry ◽  
Structural Features ◽  
Loop Region ◽  
N Terminus ◽  
Hiv 1

Abstract The viral inflammatory protein II (vMIP-II) is a mammalian chemokine homologue encoded by Kaposi’s Sarcoma-associated herpesvirus. vMIP-II shows a broad spectrum binding activity to CXC, CC and CX3C chemokine receptors. Particularly, vMIP-II binds to CXCR4 and CCR5 which are two major coreceptors for HIV-1 virus entry and infection. In our previous study, we reported an all D-amino acids peptide (DV1) derived from the N-terminus of vMIP-II showing high binding affinity to CXCR4. To study the binding mechanism of vMIP-II with CXCR4, we attached the first 10 D-amino acid residues of this peptide to the N-terminus of vMIP-II, before the first cysteine and synthesized a new chemokine analogue of vMIP-II which we named D10-vMIP-II. Despite of the chiral inverse of the N-terminal residues, D10-vMIP-II shows high CXCR4 binding affinity and inhibits the HIV-1 virus entry as vMIP-II. To explore the structural features of D10-vMIP-II, we determined its crystal structure in high resolution. The crystal structure shows that D10-vMIP-II adopts the same structural folding pattern as vMIP-II except for structural changes at the N-terminus, N-loop and the 30’s loop region, suggesting that the local structures at the N-terminus, N-Loop and the 30’s loop region can be adjusted coordinately. This novel synthetic SMM-Chemokine strongly inhibits the entry and replication of HIV-1 via CXCR4. Our studies demonstrate a new promising lead for the development of therapeutic agents targeted to the HIV-1 entry mechanism.

scholarly journals Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450

1996 ◽  
Vol 3 (4) ◽  
pp. 301-314 ◽  
Author(s):  
C. Nicholas Hodge ◽  
Paul E. Aldrich ◽  
Lee T. Bacheler ◽  
Chong-Hwan Chang ◽  
Charles J. Eyermann ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Human Pharmacokinetics ◽  
Resistance Profile ◽  
X Ray ◽  
Hiv 1
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