nearest neighbors of specific plasmodial kinases; their 3D structures are used for
finding selectivity profile at the active sites. Separately, the ATP-binding and
substrate-binding site domains of these kinases are extracted on the basis of Hunk
and Hunter classification [139], and their structures are superimposed for clustering
on the basis of RMSD matrix and are shown in Table 5 and Fig. 5.
It is interesting to note that three of the plasmodium kinases occur in the largest
cluster containing most of human kinase, like MapK and CDKs; but PfPK7 occurs
in different cluster in both ATP & substrate specific clustering, it signifies the
selective functioning of this kinase. Hence, to achieve selectivity in favor of
malarial ligand requires subsite exploitation and using appropriate designing
strategy for docking compounds in search of both specific and selective ligand. In a
recent review [39], such small active site differences are discussed under the context
of how the entropy and enthalpy balances are carried out in free energy estimation
Table 5 Selective binding site clustering using structure of human and plasmodial ser/thr kinase,
uncommon one shown in bold face font and underlined
Plasmodial
Human
Kinase domain
ATP-binding site
Substrate-binding site
Pfpk5
Pfpk6
Pfmrk
CDK5, CDC2, CDK3,
CDK9, ERK2, ERK1,
p38-c, p38-b, GSK3-b,
DYRK1A, MAPK8
p38-d, CDK5, p38-c,
CDK7, MAPK6, CDK3,
ERK2, GSK3-b,
MAPK8, CDK2, ERK1,
CDK9, p38-b, CDC2,
DYRK1A
CDK5, CDK3, ERK2,
CDK2, ERK1, p38-c,
p38-b, p38-a, p38-d,
CDC2, CDK6, PAK1
Pfpk7
MAPK6, PAK1,
PAK4, PAK7, PKC
iota
PAK1, PAK4, PAK7,
PKC iota
PAK4, PAK7, CDK9,
CDK4, PKC iota,
CDK7
Non-plasmodial
cluster
CDK2, CDK4, CDK6,
p38-a, p38-d
CDK6, Cdk4, p38-a
DYRK1A, MAPK8,
MAPK6, GSK3-b
Fig. 5 Structure-based clustering of human kinases associated with plasmodium using
a ATP-binding site and b using substrate-binding site. It clearly depicts different combinations
of selectivity (listed in Table 5)
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
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