protonation equilibria on conformational dynamics for the apo BACE-1 with fixed
protonation states for titratable residues using conventional molecular dynamics
(cMD) in acidic (pH range 1–3) and basic (pH range 9–11) conditions and observed
that in acidic condition, two major conformations open and closed were populated
while in basic condition, only widely open flap conformation was significantly
populated. In another similar in silico study, again using CpHMD replica exchange
simulation Ellis and Shen [96] reported that BACE-1 majorly occupies three
conformations (so called Tyr-inhibited, binding-competent, and Gln-inhibited) and
conformational population shift with varying pH causes the pH dependence of the
inhibitors binding affinity to BACE-1 [96]. They showed that Gln-inhibited and
binding-competent conformational states are separated by small (<1 kcal/mol) free
energy barrier, and Gln-inhibited state has consistently low population (<25%) for
entire pH range; thus, they focused on only remaining two of the conformational
states, suggesting that substrate BACE-1 binding follows a conformational selection model [96].
2.6 Effect of Solvation
Almost all biological functions occur in cytosol in cell, but some of them are
membrane-associated phenomena, water solubility of inhibitors showing significant
binding affinity toward its cognate receptor poses another challenge in SBDD [99],
since low solubility causes low bioavailability of the inhibitor to target. Similar
problem surfaced with the potent non-peptide cyclic urea analogs of HIV-1 protease
inhibitor, e.g., DMP-323, the carbonyl oxygen of cyclic urea of DMP-323 mimics a
structural water in the binding site by providing similar hydrogen-binding features
and therefore gains affinity by displacing the water. The low-molecular-weight
compound was expected to have high bioavailability [100], but unexpectedly low
bioavailability was observed later on, and poor solubility of DMP-323 in water and
lipid milieu was suggested the reason for it [99]. Therefore, to increase water
solubility, benzylic-substituted cyclic urea with strong acid or basic groups were
designed, but highly basic group analogs were unsuccessful as inhibitory effect of
such compounds is lowered by 1000-fold [99]. However, a neutral form binding,
weak-basic derivative bis-meta-aminobenzyl, i.e., DMP-450 showed enhanced
affinity. DMP-450 has enhanced water solubility and also found to show better oral
bioavailability in animal species, rat and human [99].
2.7 Covalent Inhibitors
Non-covalent inhibitors bind to the target reversibly in concentration dependent
manner. However, *30% of FDA approved drugs are covalent binders, which
make covalent bond with the target [101]. Aspirin induces irreversible acetylation
128
S. K. Panday and I. Ghosh
protonation states for titratable residues using conventional molecular dynamics
(cMD) in acidic (pH range 1–3) and basic (pH range 9–11) conditions and observed
that in acidic condition, two major conformations open and closed were populated
while in basic condition, only widely open flap conformation was significantly
populated. In another similar in silico study, again using CpHMD replica exchange
simulation Ellis and Shen [96] reported that BACE-1 majorly occupies three
conformations (so called Tyr-inhibited, binding-competent, and Gln-inhibited) and
conformational population shift with varying pH causes the pH dependence of the
inhibitors binding affinity to BACE-1 [96]. They showed that Gln-inhibited and
binding-competent conformational states are separated by small (<1 kcal/mol) free
energy barrier, and Gln-inhibited state has consistently low population (<25%) for
entire pH range; thus, they focused on only remaining two of the conformational
states, suggesting that substrate BACE-1 binding follows a conformational selection model [96].
2.6 Effect of Solvation
Almost all biological functions occur in cytosol in cell, but some of them are
membrane-associated phenomena, water solubility of inhibitors showing significant
binding affinity toward its cognate receptor poses another challenge in SBDD [99],
since low solubility causes low bioavailability of the inhibitor to target. Similar
problem surfaced with the potent non-peptide cyclic urea analogs of HIV-1 protease
inhibitor, e.g., DMP-323, the carbonyl oxygen of cyclic urea of DMP-323 mimics a
structural water in the binding site by providing similar hydrogen-binding features
and therefore gains affinity by displacing the water. The low-molecular-weight
compound was expected to have high bioavailability [100], but unexpectedly low
bioavailability was observed later on, and poor solubility of DMP-323 in water and
lipid milieu was suggested the reason for it [99]. Therefore, to increase water
solubility, benzylic-substituted cyclic urea with strong acid or basic groups were
designed, but highly basic group analogs were unsuccessful as inhibitory effect of
such compounds is lowered by 1000-fold [99]. However, a neutral form binding,
weak-basic derivative bis-meta-aminobenzyl, i.e., DMP-450 showed enhanced
affinity. DMP-450 has enhanced water solubility and also found to show better oral
bioavailability in animal species, rat and human [99].
2.7 Covalent Inhibitors
Non-covalent inhibitors bind to the target reversibly in concentration dependent
manner. However, *30% of FDA approved drugs are covalent binders, which
make covalent bond with the target [101]. Aspirin induces irreversible acetylation
128
S. K. Panday and I. Ghosh