Druggability analysis and classification of protein tyrosine phosphatase active sites

Figures & data

Figure 1 Examples of potent PTP inhibitors.

Abbreviation: PTP, protein tyrosine phosphatase.

Table 1 Median values of druggability score (Dscore) and other SiteMap factors obtained by the 17 pathogenic PTPs studied in this work

PTPs	Number of crystal structures	Median Dscore	Median pocket size (spheres)	Median SiteScore	Median enclosure score	Median philic score
PTP1B	82	0.64 (0.39–0.91)	69.5 (39–124)	0.90 (0.75–0.99)	0.71 (0.60–0.83)	1.7 (1.1–2.3)
SHP2	6	0.59 (0.51–0.70)	60.5 (55–72)	0.84 (0.82–0.87)	0.69 (0.67–0.72)	1.7 (1.5–1.9)
YopH	5	0.50 (0.37–0.68)	40 (27–94)	0.702 (0.63–1.00)	0.68 (0.66–0.77)	1.8 (1.5–2.1)
CDC25B	4	0.55 (0.19–0.87)	61.5 (20–91)	0.81 (0.51–0.97)	0.66 (0.58–0.71)	1.7 (1.4–2.0)
SHP1	3	0.78 (0.67–0.9)	76 (75–164)	0.92 (0.84–1.00)	0.70 (0.61–0.73)	1.4 (1.2–1.8)
MPtpA	2	0.38 (0.26–0.50)	50.0 (48.0–52.0)	0.81 (0.80–0.83)	0.74 (0.73–0.74)	2.2 (1.2–2.6)
HCPTPB	2	0.48 (0.46–0.49)	53.0 (52–54)	0.48 (0.46–0.49)	0.68 (0.68–0.68)	1.9 (1.8–1.9)
CD45	2	0.59 (0.57–0.6)	50.5 (50–51)	0.59 (0.57–0.6)	0.78 (0.76–0.80)	1.7 (1.6–1.8)
SptP	1	0.58	58.0	0.58	0.77	1.8
PTPε	1	0.71	59.0	0.81	0.67	1.3
LAR	1	0.68	64.0	0.85	0.69	1.5
HCPTPA	1	0.68	54.0	0.76	0.62	1.2
GLEPP-1	1	0.89	140.0	1.02	0.73	1.5
LPTP1	1	0.36	35.0	0.62	0.58	1.7
MPtpB	1	1.20	196.0	1.15	0.83	0.7
PTPσ	1	0.67	47	0.77	0.71	1.2
JSP-1	1	0.25	24.0	0.53	0.55	1.6

Note: Range in parentheses.

Abbreviation: PTPs, protein tyrosine phosphatases.

Figure 2 Box plots showing the range and distribution of druggability for each PTP across available structures passing imposed filters.

Notes: Ranked by median Dscore. Colors indicate druggability classification: purple, very druggable; blue, druggable; green, intermediate; and red, difficult.
Abbreviations: Dscore, druggability score; PTP, protein tyrosine phosphatase.

Figure 3 The binding site of four PTP classes exemplified by the surfaces of representative example.

Notes: Surface colors generated using MOE Pocket coloring: red, hydrophilic; gray, hydrophobic; white, neutral. (A) MPtpB (PDB: 2OZ5³⁷), structure representative of “very druggable”. (B) GLEPP-1 (PDB: 2GJT³⁸), structure representative of “druggable”. (C) PTPε (PDB: 2JJD³⁸), structure representative of “intermediate”. (D) JSP-1 (PDB: 1WRM³⁹), structure representative of “difficult”.
Abbreviation: PTP, protein tyrosine phosphatase.

Figure 4 The correlation between the druggability of examined PTPs and their pocket size, enclosure and hydrophilicity.

Notes: (A) The correlation between Dscore values obtained by the 17 PTPs and their pocket size and enclosure. (B) The correlation between PTPs’ Dscore values and the hydrophilicity of their pockets.
Abbreviations: Dscore, druggability score; PTP, protein tyrosine phosphatase.

Table 2 Median values for Dscore and pocket size (number of spheres) obtained by the apo form and ligand-bound form of the 17 PTPs studied here

PTPs	Number of crystal structures		Median Dscore		Median pocket size
	Apo form	Ligand-bound form	Apo form	Ligand-bound form	Apo form	Ligand-bound form
PTP1B	4	78	0.80 (0.78–0.86)	0.64 (0.39–0.91)	78.0 (78.0–86.0)	69.0 (39–124)
SHP2	4	2	0.60 (0.51–0.70)	0.59 (0.59–0.65)	59.0 (55–72)	63.0 (59–67)
YopH	1	4	0.68	0.45 (0.37–0.68)	94.0	36.5 (27–94)
CDC25B	1	3	0.33	0.76 (0.19–0.87)	40.0	83.0 (20–91)
MPtpA	1	1	0.50	0.26	48.0	52.0
SHP1	3	–	0.78 (0.67–0.9)	–	76 (75–164)	–
HCPTPB	–	2	–	0.48 (0.46–0.49)	–	53.0 (52–54)
CD45	–	2	–	0.59 (0.57–0.6)	–	50.5 (50–51)
SptP	1	–	0.58	–	58.0	–
PTPε	1	–	0.71	–	59.0	–
LAR	1	–	0.68	–	64.0	–
HCPTPA	1	–	0.68	–	54.0	–
GLEPP-1	1	–	0.89	–	140.0	–
LPTP1	–	1	–	0.36	–	35.0
MPtpB	–	1	–	1.20	–	196.0
PTPσ	1	–	0.67		47	–
JSP-1	–	1	–	0.25	–	24.0

Notes: Range in parentheses. The dash indicates no data.

Abbreviations: Dscore, druggability score; PTPs, protein tyrosine phosphatases.

Figure 5 The active site of two crystal structures of CDC25B aligned on each other.

Notes: (A) PDB: 1CWR⁴⁰ is the apo structure and shown in gold cartoon, whereas 1QB0⁴⁰ is the ligand-bound structure and shown in blue cartoon. (B) The binding pocket surface of the apo structure of CDC25B. (C) The binding pocket surface of the CDC25B ligand-bound structure.

Figure 6 Five crystal structures of YopH aligned on each other.

Notes: The apo structure (PDB: 1YPT²¹) is shown in gold cartoon; the ligand-bound structures (PDB: 1YTN,²¹ 1YTW,²¹ 1XXV,⁴¹ and 2I42¹⁵) are shown in blue cartoon.

Figure 7 Active site conformational effect on the PTP1B druggability.

Notes: (A) The active site of two crystal structures of PTP1B aligned on each other; PDB: 2HNP⁴² is the apo structure and shown in blue cartoon, whereas 1KAK²⁸ is the ligand-bound structure and shown in gold cartoon. The binding pocket surface of the (B) PTP1B apo structure and (C) PTP1B ligand-bound form.

Table 3 Median values of Dscore and other SiteMap factors obtained by the open and closed structures of PTP1B

PTPs	Number of crystal structures	Median Dscore	Median pocket size (spheres)	Median SiteScore	Median enclosure score	Median philic score
PTP1B
Open	18	0.79 (0.55–0.91)	78 (58–124)	0.91 (0.83–0.99)	0.68 (0.63–0.75)	1.5 (1.2–2.0)
Closed	64	0.61 (0.39–0.87)	67.5 (39–116)	0.89 (0.75–0.99)	0.73 (0.60–0.83)	1.77 (1.3–2.3)

Note: Range in parentheses.

Abbreviations: Dscore, druggability score; PTPs, protein tyrosine phosphatases.

Figure 8 Examples of potent PTP inhibitors belonging to different druggability class along with their experimental potency and calculated TPSA (produced by MOE¹⁶).

Notes: Very druggable – MPtpB inhibitor;⁴³ druggable – GLEPP-1 inhibitor⁴⁴ and PTP1B allosteric inhibitor;³⁵ and difficult – Cdc25b inhibitor,⁴⁵ MPtpA inhibitor,⁴⁶ YopH inhibitors,⁴⁷ and PTP1B inhibitors^48,49 (that bind to the closed or open conformation of the active site or to the allosteric site).
Abbreviations: TPSA, total polar surface area; PTP, protein tyrosine phosphatase.

Table 4 Comparison of the median values of the SiteMap druggability factors obtained by solvated and unsolvated pockets of a total number of 43 PTP1B structures

PTP1B	Median Dscore	Median pocket size (spheres)	Median SiteScore	Median enclosure score	Median philic score
Solvated	0.50 (0.33–0.80)	50 (31–101)	0.81 (0.71–0.98)	0.72 (0.63–0.81)	1.69 (1.1–2.2)
Unsolvated	0.54 (0.39–0.85)	57 (39–116)	0.85 (0.74–0.99)	0.76 (0.64–0.83)	1.82 (1.3–2.3)

Note: Range in parentheses.

Figure 9 The location of catalytic and allosteric pockets on the PTP1B structure along with their co-crystallized ligands.

Note: A closer look at the allosteric site surface (PDB: 1T48³⁴) is also illustrated.

Table 5 Comparison of druggability data obtained by the catalytic pocket allosteric pockets of PTP1B

PTP1B	Number of crystal structures	Median Dscore	Median pocket size (spheres)	Median SiteScore	Median enclosure score	Median philic score
Allosteric pocket	3	0.97 (0.85–1.04)	61 (47–225)	0.91 (0.83–1.01)	0.63 (0.63–0.69)	0.5 (0.4–0.9)
Catalytic pocket	82	0.64 (0.39–0.91)	69.5 (39–124)	0.90 (0.75–0.99)	0.71 (0.60–0.83)	1.7 (1.1–2.3)

Note: Range in parentheses.

GrundnerCPerrinDHooft van HuijsduijnenRStructural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpBStructure200715449950917437721

 PubMed Web of Science ®Google Scholar

BarrAJUgochukwuELeeWHLarge-scale structural analysis of the classical human protein tyrosine phosphatomeCell2009136235236319167335

 PubMed Web of Science ®Google Scholar

YokotaTNaraYKashimaACrystal structure of human dual specificity phosphatase, JNK stimulatory phosphatase-1, at 1.5 Å resolutionProteins200766227227817068812

 PubMed Web of Science ®Google Scholar

ReynoldsRAYemAWWolfeCLDeibelMRJrChidesterCGWatenpaughKDCrystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycleJ Mol Biol1999293355956810543950

 PubMed Web of Science ®Google Scholar

StuckeyJASchubertHLFaumanEBZhangZYDixonJESaperMACrystal structure of Yersinia protein tyrosine phosphatase at 2.5 A and the complex with tungstateNature199437064905715758052312

 PubMed Web of Science ®Google Scholar

IvanovMIStuckeyJASchubertHLSaperMABliskaJBTwo substrate-targeting sites in the Yersinia protein tyrosine phosphatase co-operate to promote bacterial virulenceMol Microbiol20055551346135615720545

 PubMed Web of Science ®Google Scholar

RCSBProtein Data Bank2015 Available from: http://www.pdb.org/Accessed December 15, 2015

 Google Scholar

BarfordDFlintAJTonksNKCrystal structure of human protein tyrosine phosphatase 1BScience19942635152139714048128219

 PubMed Web of Science ®Google Scholar

JiaZYeQDinautANStructure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimeticsJ Med Chem200144264584459411741477

 PubMed Web of Science ®Google Scholar

Chemical Computing GroupMolecular Operating EnvironmentMontreal, CanadaChemical Computing Group2015 Available from: http://www.chemcomp.com

 Google Scholar

ZengL-FXuJHeYA facile hydroxyindole carboxylic acid based focused library approach for potent and selective inhibitors of Mycobacterium protein tyrosine phosphatase BChemMedChem20138690490823568546

 PubMed Web of Science ®Google Scholar

GobertRPvan den EijndenMSzyndralewiezCGLEPP1/protein-tyrosine phosphatase φ inhibitors block chemotaxis in vitro and in vivo and improve murine ulcerative colitisJ Biol Chem200928417113851139519233845

 PubMed Web of Science ®Google Scholar

KrishnanNKovealDMillerDHTargeting the disordered C terminus of PTP1B with an allosteric inhibitorNat Chem Biol201410755856624845231

 PubMed Web of Science ®Google Scholar

ParkHLiMChoiJChoHHamSWStructure-based virtual screening approach to identify novel classes of Cdc25B phosphatase inhibitorsBioorg Med Chem Lett200919154372437519500977

 PubMed Web of Science ®Google Scholar

RawlsKATherese LangPTakeuchiJFragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpABioorg Med Chem Lett200919246851685419889539

 PubMed Web of Science ®Google Scholar

BahtaMLountosGTDyasBUtilization of nitrophenylphosphates and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis outer protein H (YopH) phosphataseJ Med Chem20115482933294321443195

 PubMed Web of Science ®Google Scholar

ShenKKengY-FWuLGuoX-LLawrenceDSZhangZ-YAcquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedureJ Biol Chem2001276473114731911584002

 PubMed Web of Science ®Google Scholar

SzczepankiewiczBGLiuGHajdukPJDiscovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategyJ Am Chem Soc2003125144087409612670229

 PubMed Web of Science ®Google Scholar

WiesmannCBarrKJKungJAllosteric inhibition of protein tyrosine phosphatase 1BNat Struct Mol Biol200411873073715258570

 PubMed Web of Science ®Google Scholar