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The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins.

Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM - F1000Res (2013)

Bottom Line: The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies.However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs.Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India ; Plant Sciences Department, University of California, Davis, CA, 95616, USA.

ABSTRACT
The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

No MeSH data available.


Related in: MedlinePlus

A scaffold congruent to the active site of Trypsin (PDBid:1A0J) in a glutaminyl cyclase (PDBid:3PB4).(a) The active site residues are marked in magenta. They are seen to be proximal to the identified scaffold. (b) Superimposition of Motif1 and the scaffold in glutaminyl cyclase. The exact pairwise interatomic distance and electrostatic potential differences are specified inTable 1.
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f3: A scaffold congruent to the active site of Trypsin (PDBid:1A0J) in a glutaminyl cyclase (PDBid:3PB4).(a) The active site residues are marked in magenta. They are seen to be proximal to the identified scaffold. (b) Superimposition of Motif1 and the scaffold in glutaminyl cyclase. The exact pairwise interatomic distance and electrostatic potential differences are specified inTable 1.

Mentions: Since both these proteins are lipases (hydrolases), this congruence to Motif1 and Motif2 is expected based on our previous results with PI-PLC22. However, our methodology also detects other proteins, often with a completely different enzymatic mechanism from hydrolases. A glutaminyl cyclase (PDBid:3PB432), a transferase, has a significantly congruent domain with Motif1 (lesser congruence with Motif2, as indicated by the RMSD) (Table 1).Figure 3 shows the proximity of the promiscuous scaffold to the active site of the cyclase, and also the congruence of the scaffold to Motif1.


The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins.

Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM - F1000Res (2013)

A scaffold congruent to the active site of Trypsin (PDBid:1A0J) in a glutaminyl cyclase (PDBid:3PB4).(a) The active site residues are marked in magenta. They are seen to be proximal to the identified scaffold. (b) Superimposition of Motif1 and the scaffold in glutaminyl cyclase. The exact pairwise interatomic distance and electrostatic potential differences are specified inTable 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4309170&req=5

f3: A scaffold congruent to the active site of Trypsin (PDBid:1A0J) in a glutaminyl cyclase (PDBid:3PB4).(a) The active site residues are marked in magenta. They are seen to be proximal to the identified scaffold. (b) Superimposition of Motif1 and the scaffold in glutaminyl cyclase. The exact pairwise interatomic distance and electrostatic potential differences are specified inTable 1.
Mentions: Since both these proteins are lipases (hydrolases), this congruence to Motif1 and Motif2 is expected based on our previous results with PI-PLC22. However, our methodology also detects other proteins, often with a completely different enzymatic mechanism from hydrolases. A glutaminyl cyclase (PDBid:3PB432), a transferase, has a significantly congruent domain with Motif1 (lesser congruence with Motif2, as indicated by the RMSD) (Table 1).Figure 3 shows the proximity of the promiscuous scaffold to the active site of the cyclase, and also the congruence of the scaffold to Motif1.

Bottom Line: The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies.However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs.Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India ; Plant Sciences Department, University of California, Davis, CA, 95616, USA.

ABSTRACT
The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

No MeSH data available.


Related in: MedlinePlus