1.5 Knowledge of Target Structure Is Essential
but not Sufficient
In spite of success in structure-based drug discovery process [29] at several occasions, knowledge about the structure of the target involved in the disease does not
necessarily lead to a drug for cure; b-Thalassemia is one such example. It is an
inherited hematologic disease caused by less b-globin, largely reported in
Mediterranean region, identified with the mutant b-globin [41]. The present treatment is continuous blood transfusions with chelation therapy [42] and less frequently, bone-marrow transplantation [43], because there is no drug treatment for
cure. However, the first crystal structure of hemoglobin was known in 1968, and
since then, more than 250 human hemoglobin structures are known [44]. Hence,
druggability and understanding of disease is a field of research in itself, emerging as
translational bioinformatics.
2 Challenges in Structure-Based Designing
As discussed in many review articles earlier, major steps to find in silico chemicals
and design them for better inhibition of target macromolecule are identification of
target protein or macromolecule of importance and associated functionally with the
disease, characterization of its 3D structure and active site, mapping of interactions
possible with chemical functional groups, docking, scoring, and finally ranking the
possible chemicals to test experimentally. Each of these steps has many challenges
which will be discussed here.
2.1 Accuracy of Structures
Before starting a docking study to screen, some library of compounds to come up
with a set of molecules showing high binding affinity with the target receptor
requires to have known 3D structure. The appropriate selection of the receptor
structure can influence the success or failure of any screening study [14]. Therefore,
a researcher needs a good structure to start with which could have been resolved
mostly using X-ray or NMR. Sometimes, the structure of the desired receptor is not
known. In such cases, a homology model of the structure can be used if a suitable
template for the receptor can be found [14]. A template may be the same protein
having similar function, showing high sequence similarity from different organism
or even some other protein having same fold. If the structure of the receptor is
known in advance, then there may be multiple structures resolved in different
conditions, with varying resolution, varying model completeness, etc. In such a
case, the most suitable structure has to be chosen [14]. In selecting receptor
116
S. K. Panday and I. Ghosh
but not Sufficient
In spite of success in structure-based drug discovery process [29] at several occasions, knowledge about the structure of the target involved in the disease does not
necessarily lead to a drug for cure; b-Thalassemia is one such example. It is an
inherited hematologic disease caused by less b-globin, largely reported in
Mediterranean region, identified with the mutant b-globin [41]. The present treatment is continuous blood transfusions with chelation therapy [42] and less frequently, bone-marrow transplantation [43], because there is no drug treatment for
cure. However, the first crystal structure of hemoglobin was known in 1968, and
since then, more than 250 human hemoglobin structures are known [44]. Hence,
druggability and understanding of disease is a field of research in itself, emerging as
translational bioinformatics.
2 Challenges in Structure-Based Designing
As discussed in many review articles earlier, major steps to find in silico chemicals
and design them for better inhibition of target macromolecule are identification of
target protein or macromolecule of importance and associated functionally with the
disease, characterization of its 3D structure and active site, mapping of interactions
possible with chemical functional groups, docking, scoring, and finally ranking the
possible chemicals to test experimentally. Each of these steps has many challenges
which will be discussed here.
2.1 Accuracy of Structures
Before starting a docking study to screen, some library of compounds to come up
with a set of molecules showing high binding affinity with the target receptor
requires to have known 3D structure. The appropriate selection of the receptor
structure can influence the success or failure of any screening study [14]. Therefore,
a researcher needs a good structure to start with which could have been resolved
mostly using X-ray or NMR. Sometimes, the structure of the desired receptor is not
known. In such cases, a homology model of the structure can be used if a suitable
template for the receptor can be found [14]. A template may be the same protein
having similar function, showing high sequence similarity from different organism
or even some other protein having same fold. If the structure of the receptor is
known in advance, then there may be multiple structures resolved in different
conditions, with varying resolution, varying model completeness, etc. In such a
case, the most suitable structure has to be chosen [14]. In selecting receptor
116
S. K. Panday and I. Ghosh