Novel cGMP Efflux Inhibitors Identified by Virtual Ligand Screening (VLS) and Confirmed by Experimental Studies

Sager, Georg; Orvoll, Elin; Lysaa, Roy; Kufareva, Irina; Abagyan, Ruben; Ravna, Aina Westrheim

doi:10.1021/jm2014666

Cited by 26 publications

(24 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, zebrafish, mouse and human ABCC5 are more closely related to one another than to other ABCC family members from the same organism (Korolnek et al, 2014), suggesting potential conservation of function. Consistent with this idea, Hs-ABCC5 has similar topology (Ravna et al, 2008;Sager et al, 2012), subcellular localization (Borst et al, 2007;Korolnek et al, 2014;Meyer Zu Schwabedissen et al, 2005;Wijnholds et al, 2000), and fluorescent substrates to sea urchin C5a. For instance, McAleer et al (1999), showed that Hs-ABCC5 strongly effluxes FDA and CMFDA, but does not efflux C-AM or rhodamine dyes.…”

Section: Evolutionary Implications Of C5a-mediated Gut Morphogenesissupporting

confidence: 55%

“…A number of studies have shown that mammalian ABCC5 transports cyclic nucleotides (Boadu and Sager, 2004;Jedlitschky et al, 2000;Meyer Zu Schwabedissen et al, 2005;Sager and Ravna, 2009;Sager et al, 2012;Wielinga et al, 2003;Wijnholds et al, 2000). cGMP is reported to be a higher-affinity substrate than cAMP, but the exact affinity of cGMP remains unclear Pratt et al, 2005;Reid et al, 2003;Wielinga et al, 2003).…”

Section: Substrates Of C5amentioning

confidence: 99%

See 1 more Smart Citation

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

et al. 2015

View full text Add to dashboard Cite

ATP-binding cassette (ABC) transporters are evolutionarily conserved proteins that pump diverse substrates across membranes. Many are known to efflux signaling molecules and are extensively expressed during development. However, the role of transporters in moving extracellular signals that regulate embryogenesis is largely unexplored. Here, we show that a mesodermal ABCC (MRP) transporter is necessary for endodermal gut morphogenesis in sea urchin embryos. This transporter, Sp-ABCC5a (C5a), is expressed in pigment cells and their precursors, which are a subset of the non-skeletogenic mesoderm (NSM) cells. C5a expression depends on Delta/Notch signaling from skeletogenic mesoderm and is downstream of Gcm in the aboral NSM gene regulatory network. Long-term imaging of development reveals that C5a knockdown embryos gastrulate, but ∼90% develop a prolapse of the hindgut by the late prism stage (∼8 h after C5a protein expression normally peaks). Since C5a orthologs efflux cyclic nucleotides, and cAMP-dependent protein kinase (Sp-CAPK/PKA) is expressed in pigment cells, we examined whether C5a could be involved in gastrulation through cAMP transport. Consistent with this hypothesis, membrane-permeable pCPT-cAMP rescues the prolapse phenotype in C5a knockdown embryos, and causes archenteron hyper-invagination in control embryos. In addition, the cAMP-producing enzyme soluble adenylyl cyclase (sAC) is expressed in pigment cells, and its inhibition impairs gastrulation. Together, our data support a model in which C5a transports sAC-derived cAMP from pigment cells to control late invagination of the hindgut. Little is known about the ancestral functions of ABCC5/MRP5 transporters, and this study reveals a novel role for these proteins in mesoderm-endoderm signaling during embryogenesis.

show abstract

Section: Evolutionary Implications Of C5a-mediated Gut Morphogenesissupporting

confidence: 55%

Section: Substrates Of C5amentioning

confidence: 99%

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Table 3 reports the binding site score for the ABCC5 model and lists the residues composing the site. Predicted active site residues like ASN 441, GLN 1138 were consistent with ABCC5 model [9].…”

Section: Resultssupporting

confidence: 58%

“…Different models of ABCC5 [9] [10] are previously presented in outward-facing conformations and inward-facing conformations based on the Staphyllococcus aureus ABC transporter Sav1866 [11], which has been crystallized in an outward-facing ATP-bound state, and on the Escherichia coli MsbA, which has been crystallized in a wide open inward-facing conformation [12]. In this study, multiple homology models of ABCC5 are constructed on the X-ray crystal structure of five different ABC transporters (PDB IDs: 4F4C, 4Q9H, 4M1M, 4M2T and 4KSD) and all models are ranked as per their structural quality.…”

Section: Introductionmentioning

confidence: 99%

Molecular Modelling of Human Multidrug Resistance Protein 5 (ABCC5)

Singh¹

2016

JBPC

View full text Add to dashboard Cite

Multidrug resistance protein 5 (MRP5/ABCC5) is a 161 kDa member of the super family of ATPbinding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively effluxing anticancer drugs. ABCC5 has also been identified as an efflux transporter of cGMP (cyclic guanosine monophosphate). Elevated intracellular levels of cGMP in cancer cells have been implicated in several clinical studies, that may induce apoptosis, and as a result many different cancer cells seem to overcome this deleterious effect by increased efflux of cGMP through ABCC5. Thus inhibition of ABCC5 may have cytotoxic effects mediated through cGMP and it will also increase the intracellular concentration of other drugs that are aimed for the treatment of cancer which are otherwise exported out of the cells. Considering the functional importance and lack of X-ray crystal structure of ABCC5, present work was undertaken to construct 3D structure of protein using homology modeling protocol of YASARA structure (V. 16.3.28). In this study, five different ABC templates (PDB ID's: 4F4C, 4Q9H, 4M1M, 4M2T and 4KSD) were used for homology modeling. Five models were constructed on each template and a hybrid model was built using all five templates. All models were refined and ranked as per their overall Z-score. The top ranked ABBC5 model was based on template 4Q9H that had 91.2% of residues in allowed regions as revealed by PROCHECK-NMR and the QMEAN score was 0.54 which indicated a reliable model. The results of the study and the proposed model can be further used for elucidating the structural and functional aspects of ABCC5 and to gain more insights to the molecular basis of ABCC5 inhibition through docking studies.

show abstract

“…LBVS explores biological data to identify known active or inactive compounds form biological data to retrieve other potentially active molecular scaffolds based on similarity measures such as common descriptor values. A combination of these two approaches has also been proposed previously [42]. Recently, SBVS has been proven to be more effective than the other traditional ways of drug discovery [30].…”

Section: Vs (Sbvs) and Ligand-based Vs (Lbvs)mentioning

confidence: 99%

Neccessasity of Bio-imaging Hybrid Approaches Accelerating Drug Discovery Process (Mini-Review)

Samardzhieva¹,

Khan²

2018

IJCA

View full text Add to dashboard Cite

Imaging technologies have made a significant improvement in the past few decades and their application made a great impact on accelerating the process of drug discovery and development. The ability to non-invasively image an animal model or co-cultured live cells and validate potential drug target, biomarkers of drug efficacy and assess a pharmacological drug interaction significantly contributes to the process of translating molecules into medicines. This paper summarizes current trends in bio-imaging technologies and their application on the process of drug discovery. In particular, High Content Screening (HCS) and Virtual Screening (VS) are reviewed, and their respective examples are discussed to gain insight into state-of-the-art bio-imaging methodologies used for extracting knowledge and its application to drug discovery. This paper argues the need to reduce the gap between experimental (e.g. HCS based assays) and theoretical (e.g. VS based assays) assays. Although HCS and VS are leading drug discovery choices for the pharmaceutical industry and such investigations have been carried out in their respective campaign, the potential effects of these approaches together to facilitate the process of drug discovery has rarely been reported. Further, the prevalent research trends on developing hybrid approaches such as VS complementing HCS implies substantial enhancement to the goal of reliable drug candidate identification.

show abstract

Novel cGMP Efflux Inhibitors Identified by Virtual Ligand Screening (VLS) and Confirmed by Experimental Studies

Cited by 26 publications

References 42 publications

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

Molecular Modelling of Human Multidrug Resistance Protein 5 (ABCC5)

Neccessasity of Bio-imaging Hybrid Approaches Accelerating Drug Discovery Process (Mini-Review)

Contact Info

Product

Resources

About