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15th October 2016 @ 06:47

Score with Cyscore v2 (http://clab.labshare.cn/software/cyscore.html). More negative scores are better.

 

MMV670652, Yasara pose 1: -6.0138

MMV670947, Yasara pose 5: -4.3997

MMV670947, Yasara pose 6: -4.5290

14th August 2016 @ 03:15

The selected pose is about equally distant from the three resistance mutations described in the Kieran Kirk paper, about 7 angstroms from Gln172, Ala353, Thr418. This further supports that the predicted pose is biologically reasonable. Attached is a figure showing the distance of MMV670947 from these three residues.

Attached Files
6th August 2016 @ 07:30

Calculate ligand strain in the predicted binding modes for MMV670652 and MMV670947. Use OpenEye Freeform (free academic license).

 

MMV670652

Yasara pose 1:Local strain: 2.9 kcal/mol. Global strain: 6.1 kcal/mol.

PNAS pose 1:Local strain: 5.7 kcal/mol. Global strain: 7.6 kcal/mol.
PNAS pose 2:Local strain: 1.4 kcal/mol. Global strain: 4.4 kcal/mol.
PNAS pose 5:Local strain: 3.2 kcal/mol. Global strain: 7.5 kcal/mol.

PNAS pose 2 also has best DSX and Pose Score. Favor PNAS pose 2 over pose 1 and 5, but still consider Yasara pose.

 

MMV670947


Yasara pose 3:Local strain: 5.8 kcal/mol. Global strain: 8.9 kcal/mol. Pose already previously rejected.
Yasara pose 4:Local strain: 5.4 kcal/mol. Global strain: 10.0 kcal/mol.
Yasara pose 5:Local strain: 3.4 kcal/mol. Global strain: 7.4 kcal/mol.
Yasara pose 6:Local strain: 2.4 kcal/mol. Global strain: 5.6 kcal/mol.

Reject pose 4 due to strain.

PNAS flex1, pose 1:Local strain: 3.4 kcal/mol. Global strain: 10.8 kcal/mol.
PNAS flex1, pose 2:Local strain: 3.2 kcal/mol. Global strain: 7.5 kcal/mol.
PNAS flex2, pose 1:Local strain: 6.8 kcal/mol. Global strain: 12.3 kcal/mol.

Reject flex1, pose1 and flex2, pose 1 due to strain.

 

Best options so far are Yasara pose 1 for MMV670652 and Yasara poses 5, 6 for MMV670947.

3rd August 2016 @ 05:29

Follow similar strategy as for MMV670947 except here we skip the initial step of performing blind docking against PfATPase4. We start with docking into the two most promising binding sites identified for MMV670947, 1) that from the Yasara homology model and 2) binding site 1 from the PNAS model.

We dock MMV670947 into the flexible receptor with Vina through Yasara. The top poses are rescored with DSX and Pose&Rank Pose Score.

 

DSX with MMV670652.

PNAS site 1, DSX, Pose score
mol2, -162.9 -43.9
mol5, -153.8 -36.5
mol1, -150.8 -33.7

yasara, DSX, Pose score

mol1, -153.0, -43.0

 

See that DSX and Pose scores are lower for MMV670652 vs MMV670947 - this is probably not meaningful.

These poses show potential specific interactions with the trazolopyrazine. The pose for the Yasara model matches the exact same site as that identified for MMV670947 although they are oriented differently rotationally. The poses for MMV670652 and 670947 in the PNAS model for site 1 do not overlap at all.

Favor Yasara site for now as the common site for both compounds.

 

Attached files are pymol session files.

Attached Files
3rd August 2016 @ 02:47

Dock MMV670947 against previously generated homology models of PfATPase4. MMV670947 has among the higest activity, ~20 nM. Hypothesize to see a common binding site for all chemically similar, high affinity compounds.

First dock MMV670947 against PfATPase4 without a specified binding site. Generate a 3D model for MMV670947 with OpenBabel. Optimize geometry with MOPAC using PM7. Treat receptor as rigid. Use Autodock Vina as implemented in Yasara. Rescore results from Yasara with DSX and Pose and Rank (Pose Score, http://modbase.compbio.ucsf.edu/ligscore/).

Top 4 solutions docked into Yasara homology model cluster into same binding site. Solutions 1,3-5 docked into PNAS homology model are in another binding site. Solution #4 yet another binding site. In summary, we have three candidate binding sites.

Redock into these binding sites allowing for flexibility of receptor side chains contacting ligand, using Vina in Yasara. Rescore in DSX and Pose and Rank (Pose Score).

 

Yasara model

cluster, DSX score, Pose Score

cluster3, -172.2, -53.3

cluster6, -170.0, -52.3

cluster4, -166.9, -46.6
cluster5, -164.2, -51.3

 

3,4,5 overlap well. 6 is rotated 180 degrees. Clusters 4,5,6 okay but Cluster 3 does not show specific interactions with triazolopyrazine.

 

PNAS model, site 1

cluster, DSX score, Pose Score

cluster1, -168.2, -35.4
cluster2, -164.7, -44.6
cluster3, -157.4, -27.4

 

1,2 overlap but are turned 180 degrees. 3 is different site. Discard #3 because of poor DSX and Pose scores. PNAS site 1, cluster 2 also does not show specific interactions with triazolopyrazine. PNAS site 1, cluster 1 is okay.

 

PNAS model, site 2

cluster, DSX score, Pose Score

cluster1, -189.1, -52.0

 

PNAS site 2, cluster 1 does not show specific interactions with triazolopyrazine. Discard.

 


Attached Files