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24th March 2015 @ 23:48

There is evidence from Kiaran Kirk's lab that Series 4 of the OSM Consortium inhibits ATP4, an ion homeostasis pump that has become an important target in antimalarial drug discovery. This importance stems from it being an apparently validated target with a candidate, KAE609, in the clinical pipieline. There are recent reports that other, very promising, compounds also hit this target (1, 2).

But because it's an integral membrane protein, there's no structure yet. So there's no direct physical evidence for a binding interaction. There are resistance studies (grow parasite with drug, develop resistance, sequence genome, observe mutations in gene relevant to ATP4) but in a recent paper it was found that resistance is also related to mutations in a second gene (for the protein PfCDPK5). A homology model has been used to build a structure for the protein in silico; analysis of where the mutations occurred (Fig 2 in the paper) seemed to suggest they cluster in a certain region, but to my eye they did not.

In a startling paper that came out last year, Kiaran Kirk, Adele Lehane and others screened the MMV Malaria Box in their phenotypic ion regulation assay. They found that a truly astonishing array of chemotypes were active - those shown below. The assignment list (i.e. which structure (given by the MMV number) belongs to which chemotype (denoted "N") is given as a list at the end of this post.

ATP4 Active Chemotypes

How is this possible? To me it's not clear.

What we need to do is build a pharmacophore model using the known actives and inactives. We had a quick, informal go at this last year in OSM, but we didn't write it up since Kiaran's paper was under embargo. We'll now get this part of the project going in the public domain in the lab notebook and invite everyone to collaborate. We need an in silico model, the list of actives/inactives, the relevant known mutations known to be associated with resistance and people willing to digest the numbers.

This issue is important because i) it'd be nice to see how these different chemotypes can bind the same protein and in so doing actually provide evidence that they *do* bind this protein, ii) we could be predictive about which molecules to make to increase the chances of securing a hit against ATP4 and iii) we could gain some clarity in whether these diverse structure possess the same mechanism of action, and therefore whether developing them all is a risk (single mutation confers resistance to multiple drug candidates).

 

Assignment List

MMV006427 N1
MMV000642 Guy Ch-I
MMV000662 Guy Ch-I
MMV0006429 Guy Ch-I
MMV011567 N2 Ch-II
MMV665805 N2 Ch-II
MMV665878 N3
MMV665800 N4 Ch-III
MMV000648 Guy Ch-I
MMV000653 Guy Ch-I
MMV665918 N5 (possible OSM S4)
MMV007617 N6
MMV665803 N4 Ch-III
MMV665796 N4 Ch-III
MMV665826 N7
MMV665890 N2 Ch-II
MMV396719 N8 Ch-IV spiro?
MMV396715 N8 Ch-IV spiro?
MMV396749 N8 Ch-IV spiro?
MMV020660 N2 Ch-II
MMV665949 N9
MMV000917 N10
MMV666025 N11
MMV008455 Guy?
MMV006764 N12
MMV007275 N13

MMV666124 N14?
MMV006656 N12

 

Compound Strings

Representative spiroindolone (KAE609) C[C@@H](C1)N[C@@]2(C(NC3=C2C=C(Cl)C=C3)=O)C4=C1C5=CC(F)=C(Cl)C=C5N4 InChI=1S/C19H14Cl2FN3O/c1-8-4-11-10-6-14(22)13(21)7-16(10)23-17(11)19(25-8)12-5-9(20)2-3-15(12)24-18(19)26/h2-3,5-8,23,25H,4H2,1H3,(H,24,26)/t8-,19+/m0/s1 CKLPLPZSUQEDRT-WPCRTTGESA-N

Representative dihydroisoquinolone (SJ733) O=C1C2=CC=CC=C2[C@H](C(NC3=CC(C#N)=C(F)C=C3)=O)[C@@H](C4=CN=CC=C4)N1CC(F)(F)F InChI=1S/C24H16F4N4O2/c25-19-8-7-16(10-15(19)11-29)31-22(33)20-17-5-1-2-6-18(17)23(34)32(13-24(26,27)28)21(20)14-4-3-9-30-12-14/h1-10,12,20-21H,13H2,(H,31,33)/t20-,21+/m0/s1 VKCPFWKTFZAOTO-LEWJYISDSA-N

Representative aminopyrazole (GNF-Pf-4492) O=C(NC1=CC=C(F)C=C1F)NC2=C(C3=CC=C(Br)C=C3)C(C(F)(F)F)=NN2C InChI=1S/C18H12BrF5N4O/c1-28-16(26-17(29)25-13-7-6-11(20)8-12(13)21)14(15(27-28)18(22,23)24)9-2-4-10(19)5-3-9/h2-8H,1H3,(H2,25,26,29) YDMCNKUCKHWGIM-UHFFFAOYSA-N

Representative OSM Series 4 (OSM-S-202) O=C(NC1=CC(Cl)=CC=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C19H12ClF2N5O2/c20-12-2-1-3-13(8-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-4-6-14(7-5-11)29-19(21)22/h1-10,19H,(H,24,28) AJGOFYWOTIIYLR-UHFFFAOYSA-N

MMV006427 O=S1(C2=CC=CC=C2C(SC(C(N(C)C3=C(OC)C=C(OC)C(Cl)=C3)=O)=C4)=C4C1)=O InChI=1S/C21H18ClNO5S2/c1-23(15-9-14(22)16(27-2)10-17(15)28-3)21(24)18-8-12-11-30(25,26)19-7-5-4-6-13(19)20(12)29-18/h4-10H,11H2,1-3H3 RXQJJBRAANNIDY-UHFFFAOYSA-N

MMV011567 O=C(C1=CC(Cl)=C(OC)C=C1)NC2=NON=C2C3=CC=C(OC)C(OC)=C3 InChI=1S/C18H16ClN3O5/c1-24-13-6-5-11(8-12(13)19)18(23)20-17-16(21-27-22-17)10-4-7-14(25-2)15(9-10)26-3/h4-9H,1-3H3,(H,20,22,23) RUPCNQRICRCGRU-UHFFFAOYSA-N

MMV665878 O=C1N([C@H](C(NC2=CC(OC)=CC=C2)=O)C(C)C)C(C3=CC=CC=C3N1)=O InChI=1S/C20H21N3O4/c1-12(2)17(18(24)21-13-7-6-8-14(11-13)27-3)23-19(25)15-9-4-5-10-16(15)22-20(23)26/h4-12,17H,1-3H3,(H,21,24)(H,22,26)/t17-/m0/s1 HGHQOEUVKUMVFT-KRWDZBQOSA-N

MMV665800 CC(C1=CC(OCC)=C(OCC)C=C1Cl)NC(C2=CC=CC=C2)=O InChI=1S/C19H22ClNO3/c1-4-23-17-11-15(16(20)12-18(17)24-5-2)13(3)21-19(22)14-9-7-6-8-10-14/h6-13H,4-5H2,1-3H3,(H,21,22) LAXUZBKJDUGZGQ-UHFFFAOYSA-N

MMV665918 FC1=CC(C2=NN=C3N2N=C(SCC(NC4=CC(OCO5)=C5C=C4)=O)C=C3)=CC=C1 InChI=1S/C20H14FN5O3S/c21-13-3-1-2-12(8-13)20-24-23-17-6-7-19(25-26(17)20)30-10-18(27)22-14-4-5-15-16(9-14)29-11-28-15/h1-9H,10-11H2,(H,22,27) HCHXPMOIMAHZOG-UHFFFAOYSA-N

MMV007617 CC(NCCC1=NC2=C(N1CC3=CC=C(C(C)C)C=C3)C=CC=C2)=O InChI=1S/C21H25N3O/c1-15(2)18-10-8-17(9-11-18)14-24-20-7-5-4-6-19(20)23-21(24)12-13-22-16(3)25/h4-11,15H,12-14H2,1-3H3,(H,22,25) VLJWUPFUQDYBCW-UHFFFAOYSA-N

MMV665826 CC1=C(C#N)C2=C(N1CC(NC3=CC=CC(OC)=C3)=O)C=CC=C2 InChI=1S/C19H17N3O2/c1-13-17(11-20)16-8-3-4-9-18(16)22(13)12-19(23)21-14-6-5-7-15(10-14)24-2/h3-10H,12H2,1-2H3,(H,21,23) MEDFKFHQIXAAGU-UHFFFAOYSA-N

MMV396719 CC(NC1=C2C=CC=C1)(C3=CC=CC(OC)=C3)N(C2=N4)C5=C4C=CC=C5 InChI=1S/C22H19N3O/c1-22(15-8-7-9-16(14-15)26-2)24-18-11-4-3-10-17(18)21-23-19-12-5-6-13-20(19)25(21)22/h3-14,24H,1-2H3 GOFKBYMLZNXKGI-UHFFFAOYSA-N

MMV665949 Cl/C(Cl)=C(C1=CC=C(O)C=C1)/C2=CC=C(O)C=C2 InChI=1S/C14H10Cl2O2/c15-14(16)13(9-1-5-11(17)6-2-9)10-3-7-12(18)8-4-10/h1-8,17-18H OWEYKIWAZBBXJK-UHFFFAOYSA-N

MMV000917 O=C1N2C3=CC=CC=C3N=C(C4=CC=C(C)C=C4)CC2C5=C1C(OC)=C(OC)C=C5 InChI=1S/C25H22N2O3/c1-15-8-10-16(11-9-15)19-14-21-17-12-13-22(29-2)24(30-3)23(17)25(28)27(21)20-7-5-4-6-18(20)26-19/h4-13,21H,14H2,1-3H3 CFQPOWRJAPPJEW-UHFFFAOYSA-N

MMV666025 BrC1=CC(C(C=C(Br)C=C2)=C2N3CC(CN4N=NC5=C4C=CC=C5)O)=C3C=C1 InChI=1S/C21H16Br2N4O/c22-13-5-7-19-16(9-13)17-10-14(23)6-8-20(17)26(19)11-15(28)12-27-21-4-2-1-3-18(21)24-25-27/h1-10,15,28H,11-12H2 UKHSRZJVKOZGAD-UHFFFAOYSA-N

MMV006764 CN1C=C(C(OC)=O)C(C2=CC(OC)=C(OCC)C(Br)=C2)C(C(OC)=O)=C1 InChI=1S/C19H22BrNO6/c1-6-27-17-14(20)7-11(8-15(17)24-3)16-12(18(22)25-4)9-21(2)10-13(16)19(23)26-5/h7-10,16H,6H2,1-5H3 GHWXGIMICMXCPZ-UHFFFAOYSA-N

MMV007275 ClC(C=C1C(NC2=C(C)C=CC(F)=C2)=O)=CC=C1NC3=CC=CC=C3 InChI=1S/C20H16ClFN2O/c1-13-7-9-15(22)12-19(13)24-20(25)17-11-14(21)8-10-18(17)23-16-5-3-2-4-6-16/h2-12,23H,1H3,(H,24,25) YDYIMBIBJGKUCE-UHFFFAOYSA-N

MMV666124 O=C(NC1=CC=C(C(C)=O)C=C1)CSC2=NC(C3=C(Cl)C=CC=C3)=NS2 InChI=1S/C18H14ClN3O2S2/c1-11(23)12-6-8-13(9-7-12)20-16(24)10-25-18-21-17(22-26-18)14-4-2-3-5-15(14)19/h2-9H,10H2,1H3,(H,20,24) QHKAIZZULJHVRC-UHFFFAOYSA-N

Attached Files
ATP4 Chemotypes 2.cdxml
ATP4 Chemotypes 2.png