3000,000 frames. Every 100th frame was taken for MM-PBSA analysis using
MMPBSA.py [239] program in AmberTools14 [233].
The gas phase binding energy DE MM was highest for INR followed by STA,
PVB, and OLM, but the solvation penalty was also highest for INR and least for
STA. In terms of enthalpy of binding, STA was predicted to be best, followed by
PVB, INR, and OLM, respectively. The inconsistency of binding enthalpy with
IC 50 indicates possible role of entropy in this case. There may be role of solvation
as well which is not rigorously captured in solvation terms considered proportional
to buried surface area on binding in MM-PBSA method; see Table 12.
However, it may be criticized that selected docking programs use different
scoring, therefore to be able to assess their performance as well as compare with
experiment values is not possible. So, another attempt was done by normalizing all
the scores, by converting all of them to positive scores (normalized using
(score − min score )/(max score − min score )). This yields a consistent normalized score,
where weakest and strongest binder ligands get normalized scores ranging 0 and 1,
respectively. Same is used for normalizing experimental values, i.e., RTln(IC 50 ).
Results are shown in Fig. 12, Dock6 predicted scores for all ligands are within
1-sigma range, Gold and LibDock each predicted one outlier, and Glide predicted
two outlier scores. In present case, Dock6, Gold, and LibDock appear to perform
better than Glide. These results may not be sufficient to capture docking/scoring
capabilities of chosen programs, as only four ligands are studied and they bind to
only one target. A more diverse target set and a large ligand set could better
comprehend the features and/or limitation of individual programs; this will be
discussed later also.
The binding enthalpy predicted using MM-PBSA method consists of two outliers from 1−r range (computed as discussed earlier), and it does not agree fully
with docking scores obtained from any of the four chosen programs, as expected.
However, strong and weak binders predicted using MM-PBSA is same as predicted
by LibDock, and second strong binder predicted using these two is similar in
affinity. While MM-PBSA results agree with Gold results for two weak binders and
not for strong binders. Glide agrees on experimentally found strong and weak
binders with MM-PBSA. Score using Dock6 agrees better than MM-PBSA
(Fig. 12). As observed in the present case, the scoring by Docking methods as well
Table 12 Enthalpy component of binding free of selected inhibitors of PfPK5, calculated using
MM-PBSA method
Inhibitor
IC 50 (in nM)
RT ln(IC 50 )
(kcal/mol)
Predicted (kcal/mol)
DE MM
DG Solv
Total: DH PBSA
OLM
15,000
−6.622
−58.5 ± 7.9
25.4 ± 5.9
−33.1 ± 4.1
INR
5500
−7.220
−102.7 ± 8.7
62.4 ± 5.9
−40.3 ± 4.2
STA
1000
−8.236
−69.0 ± 5.5
19.8 ± 4.0
−49.2 ± 4.7
PVB
130
−9.453
−65.7 ± 8.9
22.6 ± 6.0
−43.1 ± 4.7
These values are computed for 3000 snapshots extracted from 3-ls-long MD simulations for each
inhibitors in complex with PfPK5, internal dielectric constant was taken 2, and ionic strength zero
154
S. K. Panday and I. Ghosh
MMPBSA.py [239] program in AmberTools14 [233].
The gas phase binding energy DE MM was highest for INR followed by STA,
PVB, and OLM, but the solvation penalty was also highest for INR and least for
STA. In terms of enthalpy of binding, STA was predicted to be best, followed by
PVB, INR, and OLM, respectively. The inconsistency of binding enthalpy with
IC 50 indicates possible role of entropy in this case. There may be role of solvation
as well which is not rigorously captured in solvation terms considered proportional
to buried surface area on binding in MM-PBSA method; see Table 12.
However, it may be criticized that selected docking programs use different
scoring, therefore to be able to assess their performance as well as compare with
experiment values is not possible. So, another attempt was done by normalizing all
the scores, by converting all of them to positive scores (normalized using
(score − min score )/(max score − min score )). This yields a consistent normalized score,
where weakest and strongest binder ligands get normalized scores ranging 0 and 1,
respectively. Same is used for normalizing experimental values, i.e., RTln(IC 50 ).
Results are shown in Fig. 12, Dock6 predicted scores for all ligands are within
1-sigma range, Gold and LibDock each predicted one outlier, and Glide predicted
two outlier scores. In present case, Dock6, Gold, and LibDock appear to perform
better than Glide. These results may not be sufficient to capture docking/scoring
capabilities of chosen programs, as only four ligands are studied and they bind to
only one target. A more diverse target set and a large ligand set could better
comprehend the features and/or limitation of individual programs; this will be
discussed later also.
The binding enthalpy predicted using MM-PBSA method consists of two outliers from 1−r range (computed as discussed earlier), and it does not agree fully
with docking scores obtained from any of the four chosen programs, as expected.
However, strong and weak binders predicted using MM-PBSA is same as predicted
by LibDock, and second strong binder predicted using these two is similar in
affinity. While MM-PBSA results agree with Gold results for two weak binders and
not for strong binders. Glide agrees on experimentally found strong and weak
binders with MM-PBSA. Score using Dock6 agrees better than MM-PBSA
(Fig. 12). As observed in the present case, the scoring by Docking methods as well
Table 12 Enthalpy component of binding free of selected inhibitors of PfPK5, calculated using
MM-PBSA method
Inhibitor
IC 50 (in nM)
RT ln(IC 50 )
(kcal/mol)
Predicted (kcal/mol)
DE MM
DG Solv
Total: DH PBSA
OLM
15,000
−6.622
−58.5 ± 7.9
25.4 ± 5.9
−33.1 ± 4.1
INR
5500
−7.220
−102.7 ± 8.7
62.4 ± 5.9
−40.3 ± 4.2
STA
1000
−8.236
−69.0 ± 5.5
19.8 ± 4.0
−49.2 ± 4.7
PVB
130
−9.453
−65.7 ± 8.9
22.6 ± 6.0
−43.1 ± 4.7
These values are computed for 3000 snapshots extracted from 3-ls-long MD simulations for each
inhibitors in complex with PfPK5, internal dielectric constant was taken 2, and ionic strength zero
154
S. K. Panday and I. Ghosh