done using reproduction of geometry from complexed crystal structure, comparing
close relation with binding affinity (experimental) and scoring and ranking and two
other important parameters known as enrichment factors (EF) and receiving operators characteristic (ROC) [176–178].
4.3 Does Scoring Function Reflect Binding Activity?
Scoring functions can only predict the binding affinity of a receptor with its ligands
in isolation [156], but the cellular environment is significantly different, where it
may be interacting with other molecules which may alter its affinity toward its
ligand, e.g., activation of tumor suppressor protein p53 activation is regulated by
MDM2/MDMX [74]. Inhibition measure of a ligand for its receptor is the end result
of several pharmacokinetic factors as well other than affinity, e.g., bioavailability
[73, 99]. Therefore, docking score of a ligand for its receptor may not be the actual
measure of its inhibitory potential always. The similar kind of evidence emerged,
when it was noticed that urea analog DMP-323 had shown good affinity and predicted inhibitory potential for HIV-1 protease [100], but it could not succeed
because of its very low bioavailability due to its poor solubility [99]. In the
follow-up study, a new analog DMP-450 with higher water solubility was designed
and found to show better inhibition of HIV-1 protease [99]. As detailed in Sect. 2.3,
in the similar way to save from proteolytic cleavage, a-helical clipped peptide was
designed from human serum protein HSP’s variants, as inhibitor of the MDM2 and
MDMX complex [73]. The proteolytic cleavage was hampering its bioavailability;
thus, clipped a-helical peptide achieved improved pharmacokinetics, thus ensured
better efficacy in human and rat models [73].
5 Limitations of Methods
5.1 Appropriate Structure of Receptor to Select
While selecting a receptor structure for initiating docking study, parameters listed in
Table 1 can be used to prioritize structures if more than one structure is available,
and to choose appropriate structure. In present case, we have summarized some of
the structure validation results for two different structures of HIV-1 protease (PDB
ids: 1FQX and 4ZIP) in Fig. 8 and crystal structure details shown in Table 6.
Analysis of structures is available from RSCB PDB [179] (https://files.rcsb.org/pub/
pdb/validation_reports/fq/1fqx/1fqx_full_validation.pdf and https://files.rcsb.org/
pub/pdb/validation_reports/zi/4zip/4zip_full_validation.pdf).
In general, structure for which different parameter values are in blue zone in
horizontal bars for it is preferable. These horizontal bars represent statistical likelihood of reported structure to be in acceptable/unacceptable range. The range of
140
S. K. Panday and I. Ghosh
close relation with binding affinity (experimental) and scoring and ranking and two
other important parameters known as enrichment factors (EF) and receiving operators characteristic (ROC) [176–178].
4.3 Does Scoring Function Reflect Binding Activity?
Scoring functions can only predict the binding affinity of a receptor with its ligands
in isolation [156], but the cellular environment is significantly different, where it
may be interacting with other molecules which may alter its affinity toward its
ligand, e.g., activation of tumor suppressor protein p53 activation is regulated by
MDM2/MDMX [74]. Inhibition measure of a ligand for its receptor is the end result
of several pharmacokinetic factors as well other than affinity, e.g., bioavailability
[73, 99]. Therefore, docking score of a ligand for its receptor may not be the actual
measure of its inhibitory potential always. The similar kind of evidence emerged,
when it was noticed that urea analog DMP-323 had shown good affinity and predicted inhibitory potential for HIV-1 protease [100], but it could not succeed
because of its very low bioavailability due to its poor solubility [99]. In the
follow-up study, a new analog DMP-450 with higher water solubility was designed
and found to show better inhibition of HIV-1 protease [99]. As detailed in Sect. 2.3,
in the similar way to save from proteolytic cleavage, a-helical clipped peptide was
designed from human serum protein HSP’s variants, as inhibitor of the MDM2 and
MDMX complex [73]. The proteolytic cleavage was hampering its bioavailability;
thus, clipped a-helical peptide achieved improved pharmacokinetics, thus ensured
better efficacy in human and rat models [73].
5 Limitations of Methods
5.1 Appropriate Structure of Receptor to Select
While selecting a receptor structure for initiating docking study, parameters listed in
Table 1 can be used to prioritize structures if more than one structure is available,
and to choose appropriate structure. In present case, we have summarized some of
the structure validation results for two different structures of HIV-1 protease (PDB
ids: 1FQX and 4ZIP) in Fig. 8 and crystal structure details shown in Table 6.
Analysis of structures is available from RSCB PDB [179] (https://files.rcsb.org/pub/
pdb/validation_reports/fq/1fqx/1fqx_full_validation.pdf and https://files.rcsb.org/
pub/pdb/validation_reports/zi/4zip/4zip_full_validation.pdf).
In general, structure for which different parameter values are in blue zone in
horizontal bars for it is preferable. These horizontal bars represent statistical likelihood of reported structure to be in acceptable/unacceptable range. The range of
140
S. K. Panday and I. Ghosh