Chemogenomic Protein-Family Methods in Drug Discovery: Profile-QSAR and Kinase-Kernel

2013 ◽  
pp. 77-128 ◽  
Keyword(s):  
Drug Discovery ◽  
Protein Family

scholarly journals Pushing The Limits Of Detection Of Weak Binding Using Fragment Based Drug Discovery: Identification Of New Cyclophilin Binders

2017 ◽  
Author(s):  
Charis Georgiou ◽  
Iain W. McNae ◽  
Martin A. Wear ◽  
Harris Ioannidis ◽  
Julien Michel ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Dissociation Constants ◽  
Md Simulations ◽  
Detailed Comparison ◽  
Protein Family ◽  
Computational Techniques ◽  
X Ray Diffraction ◽  
Drug Candidates ◽  
Weak Binding ◽  
Fragment Based Drug Discovery

Fragment Based Drug Discovery (FBDD) is an increasingly popular method to identify novel small-molecule drug candidates. One of the limitations of the approach is the difficulty of accurately characterizing weak binding events. This work reports a combination of X-ray diffraction, surface plasmon resonance (SPR) experiments and molecular dynamics (MD) simulations, for the characterisation of binders to different isoforms of the cyclophilin (Cyp) protein family. Although several Cyp inhibitors have been reported in the literature, it has proven challenging to achieve high binding selectivity for different isoforms of this protein family. The present studies have led to the identification of several structurally novel fragments that bind to diverse Cyp isoforms in distinct pockets with low millimolar dissociation constants. A detailed comparison of the merits and drawbacks of the experimental and computational techniques is presented, and emerging strategies for designing ligands with enhanced isoform specificity are described.

scholarly journals Enabling drug discovery for the PARP protein family through the detection of mono-ADP-ribosylation

2019 ◽  
Vol 167 ◽  
pp. 97-106 ◽  
Author(s):  
Alvin Z. Lu ◽  
Ryan Abo ◽  
Yue Ren ◽  
Bin Gui ◽  
Jan-Rung Mo ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Family ◽  
Adp Ribosylation

Investigating the functional link between TMEM165 and SPCA1

2019 ◽  
Vol 476 (21) ◽  
pp. 3281-3293 ◽  
Author(s):  
Elodie Lebredonchel ◽  
Marine Houdou ◽  
Hans-Heinrich Hoffmann ◽  
Kateryna Kondratska ◽  
Marie-Ange Krzewinski ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Complete Loss ◽  
Protein Family ◽  
Uncharacterized Protein ◽  
Functional Link ◽  
P Type

TMEM165 was highlighted in 2012 as the first member of the Uncharacterized Protein Family 0016 (UPF0016) related to human glycosylation diseases. Defects in TMEM165 are associated with strong Golgi glycosylation abnormalities. Our previous work has shown that TMEM165 rapidly degrades with supraphysiological manganese supplementation. In this paper, we establish a functional link between TMEM165 and SPCA1, the Golgi Ca2+/Mn2+ P-type ATPase pump. A nearly complete loss of TMEM165 was observed in SPCA1-deficient Hap1 cells. We demonstrate that TMEM165 was constitutively degraded in lysosomes in the absence of SPCA1. Complementation studies showed that TMEM165 abundance was directly dependent on SPCA1's function and more specifically its capacity to pump Mn2+ from the cytosol into the Golgi lumen. Among SPCA1 mutants that differentially impair Mn2+ and Ca2+ transport, only the Q747A mutant that favors Mn2+ pumping rescues the abundance and Golgi subcellular localization of TMEM165. Interestingly, the overexpression of SERCA2b also rescues the expression of TMEM165. Finally, this paper highlights that TMEM165 expression is linked to the function of SPCA1.

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