of a serine residue (Ser516) in the cyclooxygenase site of the human prostaglandin
endoperoxide H synthase-2 (hPGHS-2) [102], b-lactam antibacterials forms covalent bond with the active site serine of penicillin-binding proteins which inhibits
cell wall synthesis of bacteria and causes its death, and tetrahydrolipstatin a fat
absorption inhibitors acts by inhibiting activity of pancreatic lipase [103]; these are
among the blockbuster drugs and examples of covalent inhibitors. Although
non-covalent docking is more common, recently resurgence of covalent docking
has been observed [101]. The covalent docking is more complicated mainly
because their action between receptor and ligand has to be taken care of. Selectivity
of the inhibitor toward target is important to avoid cross-reactivity. However,
selective targeting via ligands equipped with different warheads makes covalent
inhibition important [104]. In covalent inhibition, an electrophilic ligand binds to a
nucleophilic target receptor via forming a covalent bond. Theory and application
aspects of covalent docking have been reviewed elsewhere [101]. A comparative
study of recent methods and tools, e.g., CovDock [105], AutoDock4 [106],
FITTED [107], MOE [108], ICP-Pro [109], and GOLD [110] for covalent docking
has also been recently published [104].
2.8 Functionally Relevant Structure
Biologically important molecules are involved in very diverse functions and possess the structural, modular, and interactional diversity to carry their functions in the
cell. Numerous enzymes are monomer, while several of them are functional only as
homo-/hetero-multimeric forms, e.g., PNP is a homotrimer [29], HIV-1 protease is
a homodimer but has slight difference in structural features of the two monomers
[90]. A large number of macromolecules catalyze enzymatic reactions, e.g.,
BACE-1 is responsible for catalyzing hydrolytic cleavage of amyloid precursor
protein (APP) [111], some of them modulate their functions, e.g., MDMX/MDM2
complex suppresses activity of p53 and activate p53 pathway in tumor cells [74],
some of them regulate, and some of them are not related to enzymatic activities at
all, like ion channels and signaling related proteins. When we are designing
structure-based drug, we are to face challenges posed by structural, functional, and
reactional mechanistic diversity of target molecules as well.
The purine nucleoside phosphorylase (PNP) is a homotrimer and hosts three
active sites each near the interface between two monomers, with monomer consisting an a/b-fold formed from a b-sheet of four strands, a b-sheet of six strands
forming a distorted barrel, and eight a-helices [34]. The interaction between
monomers will influence the binding of ligands.
HIV-1 protease is a homodimer consisting of 198 residues. McCammon and
co-workers proposed a terminology to describe the topology as follows: flap
(43–58), ear (35–42), cheek (cheek turn = 11–22 and cheek sheet = 59–75), eye
(23–30), and nose (6–10) [112]. The active site of HIV-1 protease is covered by
b-hairpin flaps of the two monomers and is involved in controlling polypeptides’
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
129
endoperoxide H synthase-2 (hPGHS-2) [102], b-lactam antibacterials forms covalent bond with the active site serine of penicillin-binding proteins which inhibits
cell wall synthesis of bacteria and causes its death, and tetrahydrolipstatin a fat
absorption inhibitors acts by inhibiting activity of pancreatic lipase [103]; these are
among the blockbuster drugs and examples of covalent inhibitors. Although
non-covalent docking is more common, recently resurgence of covalent docking
has been observed [101]. The covalent docking is more complicated mainly
because their action between receptor and ligand has to be taken care of. Selectivity
of the inhibitor toward target is important to avoid cross-reactivity. However,
selective targeting via ligands equipped with different warheads makes covalent
inhibition important [104]. In covalent inhibition, an electrophilic ligand binds to a
nucleophilic target receptor via forming a covalent bond. Theory and application
aspects of covalent docking have been reviewed elsewhere [101]. A comparative
study of recent methods and tools, e.g., CovDock [105], AutoDock4 [106],
FITTED [107], MOE [108], ICP-Pro [109], and GOLD [110] for covalent docking
has also been recently published [104].
2.8 Functionally Relevant Structure
Biologically important molecules are involved in very diverse functions and possess the structural, modular, and interactional diversity to carry their functions in the
cell. Numerous enzymes are monomer, while several of them are functional only as
homo-/hetero-multimeric forms, e.g., PNP is a homotrimer [29], HIV-1 protease is
a homodimer but has slight difference in structural features of the two monomers
[90]. A large number of macromolecules catalyze enzymatic reactions, e.g.,
BACE-1 is responsible for catalyzing hydrolytic cleavage of amyloid precursor
protein (APP) [111], some of them modulate their functions, e.g., MDMX/MDM2
complex suppresses activity of p53 and activate p53 pathway in tumor cells [74],
some of them regulate, and some of them are not related to enzymatic activities at
all, like ion channels and signaling related proteins. When we are designing
structure-based drug, we are to face challenges posed by structural, functional, and
reactional mechanistic diversity of target molecules as well.
The purine nucleoside phosphorylase (PNP) is a homotrimer and hosts three
active sites each near the interface between two monomers, with monomer consisting an a/b-fold formed from a b-sheet of four strands, a b-sheet of six strands
forming a distorted barrel, and eight a-helices [34]. The interaction between
monomers will influence the binding of ligands.
HIV-1 protease is a homodimer consisting of 198 residues. McCammon and
co-workers proposed a terminology to describe the topology as follows: flap
(43–58), ear (35–42), cheek (cheek turn = 11–22 and cheek sheet = 59–75), eye
(23–30), and nose (6–10) [112]. The active site of HIV-1 protease is covered by
b-hairpin flaps of the two monomers and is involved in controlling polypeptides’
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
129