access to the active site before binding and closing the active site during the
cleavage and then release of the cleaved substrates. The flexibility of the flap plays
a crucial role in the catalytic activity of the enzyme [113].
Isocitrate dehydrogenases (ICDs) are another group of interesting enzymes with
two isoforms—one NADP
+
-dependent homodimer and another NAD
+
-dependent
heterotetrametric isoform consisting of two a-subunits one b-subunit and one
c-subunit. As observed in understanding the mechanism of action during phosphorylation, the structural motions facilitate the flap to cover or open the active site,
thus providing two different structures of dimmers; hence, the designing needs to
take care of such two state structures of receptor [61].
3 Mapping Interaction at Binding Site
The primary focus of structural biology has been to study the relationship between
structure and function of macromolecules. The evolution of protein structure to
confer specificity and affinity is still not completely understood. Analysis of related
structures has potential to yield local structural regions which are conserved and
those which diverge. Such knowledge can potentially be translated into understanding proteins evolution to attain specificity or protein acquiring completely new
function by matching curvature along the protein backbone to find structurally
active site regions [114].
3.1 Identification of Active Site or Binding Site
The binding sites of most proteins are extremely specific and can determine even very
small structural differences among putative binding patterns [114]. Folding of a
protein can be considered to be a process which generates specific binding site or
cavity from an unstructured polymer, driven and stabilized by thermodynamic forces
[115]. Knowledge of protein cavities provide clue about the structure and shape of
binding molecule [116]. Ligand-binding sites of protein provide insights to its biological function and reaction mechanism. Identification and application of druggable
active sites of target proteins are pivotal in in silico drug design [117]. A very diverse
active site of a protein is particularly useful for target-based drug discovery as it serves
as a prerequisite for protein–ligand docking, which is integral part of structure-based
drug design. Accurately predicting the binding modes of inhibitors in the active sites
of protein is still observed as a challenge in drug discovery [10].
All the methods which identify the active site of receptor use the concept of
accessible surface area as defined by Lee and Richards [118]. The accessible surface (ASA), also known as solvent-accessible surface area (SASA) if water is used
as the probe, of a protein is stated as the locus of the center of the solvent molecule
as it rolls along the protein, making the maximum permitted van der Waals contacts
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S. K. Panday and I. Ghosh
cleavage and then release of the cleaved substrates. The flexibility of the flap plays
a crucial role in the catalytic activity of the enzyme [113].
Isocitrate dehydrogenases (ICDs) are another group of interesting enzymes with
two isoforms—one NADP
+
-dependent homodimer and another NAD
+
-dependent
heterotetrametric isoform consisting of two a-subunits one b-subunit and one
c-subunit. As observed in understanding the mechanism of action during phosphorylation, the structural motions facilitate the flap to cover or open the active site,
thus providing two different structures of dimmers; hence, the designing needs to
take care of such two state structures of receptor [61].
3 Mapping Interaction at Binding Site
The primary focus of structural biology has been to study the relationship between
structure and function of macromolecules. The evolution of protein structure to
confer specificity and affinity is still not completely understood. Analysis of related
structures has potential to yield local structural regions which are conserved and
those which diverge. Such knowledge can potentially be translated into understanding proteins evolution to attain specificity or protein acquiring completely new
function by matching curvature along the protein backbone to find structurally
active site regions [114].
3.1 Identification of Active Site or Binding Site
The binding sites of most proteins are extremely specific and can determine even very
small structural differences among putative binding patterns [114]. Folding of a
protein can be considered to be a process which generates specific binding site or
cavity from an unstructured polymer, driven and stabilized by thermodynamic forces
[115]. Knowledge of protein cavities provide clue about the structure and shape of
binding molecule [116]. Ligand-binding sites of protein provide insights to its biological function and reaction mechanism. Identification and application of druggable
active sites of target proteins are pivotal in in silico drug design [117]. A very diverse
active site of a protein is particularly useful for target-based drug discovery as it serves
as a prerequisite for protein–ligand docking, which is integral part of structure-based
drug design. Accurately predicting the binding modes of inhibitors in the active sites
of protein is still observed as a challenge in drug discovery [10].
All the methods which identify the active site of receptor use the concept of
accessible surface area as defined by Lee and Richards [118]. The accessible surface (ASA), also known as solvent-accessible surface area (SASA) if water is used
as the probe, of a protein is stated as the locus of the center of the solvent molecule
as it rolls along the protein, making the maximum permitted van der Waals contacts
130
S. K. Panday and I. Ghosh