computational methods may only provide a core structure of a drug molecule. This
basic molecule can be altered to reduce its side effects by increasing the specificity,
efficiency in bonding pattern, change in molecule weight, and so on. In overcoming
the hurdles during high-throughput screening process in identification of good lead
compound, shaping and building the core molecule architecture through
step-by-step substructure improvement was introduced. This process is called
fragment-based drug development. This method of sculpturing of molecule for
increased efficiency was first developed by Fesik group around 1996 [124].
A similar initiative was introduced well ahead by Hol et al., during 1990 [125]. This
approach has come a long way in various procedures specifically adopted in
identification of less complex, more specific small molecule with accepted
molecular weight which binds to both protein and DNA molecules. The
fragment-based drug identification is complemented with many structural characterization methods such as fragment-based approach which has also a crucial role in
identification of lead molecules for unconventional targets [126–128], to identify
chemical probes of biological systems [129, 130].
A two-way approach exists in implementing the fragment-based method. Here,
the first case screening will be carried out to analyze a small set of compounds with
lower molecular weight to understand the binding mode against a protein site. The
molecular weight range of these compounds should be manageably good enough to
possess interaction and not large to overcome unfavorable interactions. In the
second phase, these small substructures are optimized to lead compound by addition or inclusion of properties of individual molecules so as to obtain a
better-optimized ligand. Different steps or doorways are present in developing lead
using fragment method, starting with library, method in identifying the interacting
fragment with protein target, structural analysis of such bound fragment, choosing
best fragment, and building the fragment into lead compound. This method largely
draws its structural and interaction information from X-ray crystallography, NMR,
surface plasma resonance, and other biophysical techniques.
The greater advantage of using the fragment-based method in drug discovery
strategies is its success in varied targets where regular high-throughput screening
fails. The targets may include large multimeric proteins, protein–protein complexes,
ubiquitin-specific proteases, etc. [131].
With a few slight variations in the workflow, the basic approach for
Fragment-Based Method (FBM) was well derived by the wake of the twenty-first
century [132–134]. The increased use of surface plasma resonance (SPR) has
boosted the fragment approach to new heights with rigorous and better fragment
binding understanding [135, 136]. In addition, many developments in implementation of other techniques such as immobilization of the protein and its reorganization by ligand using optical, NMR, mass spectrum, and other fluorescent-based
techniques [137–140] had happened.
FBM has helped in the identification and development of an FDA-approved drug
[141], and much more are in clinical trials [142]. Integration of FBM with SBDD in
identification of appropriate scaffold can significantly increase the result rate.
It should be noted that the importance and significance of small units
286
D. Velmurugan et al.
basic molecule can be altered to reduce its side effects by increasing the specificity,
efficiency in bonding pattern, change in molecule weight, and so on. In overcoming
the hurdles during high-throughput screening process in identification of good lead
compound, shaping and building the core molecule architecture through
step-by-step substructure improvement was introduced. This process is called
fragment-based drug development. This method of sculpturing of molecule for
increased efficiency was first developed by Fesik group around 1996 [124].
A similar initiative was introduced well ahead by Hol et al., during 1990 [125]. This
approach has come a long way in various procedures specifically adopted in
identification of less complex, more specific small molecule with accepted
molecular weight which binds to both protein and DNA molecules. The
fragment-based drug identification is complemented with many structural characterization methods such as fragment-based approach which has also a crucial role in
identification of lead molecules for unconventional targets [126–128], to identify
chemical probes of biological systems [129, 130].
A two-way approach exists in implementing the fragment-based method. Here,
the first case screening will be carried out to analyze a small set of compounds with
lower molecular weight to understand the binding mode against a protein site. The
molecular weight range of these compounds should be manageably good enough to
possess interaction and not large to overcome unfavorable interactions. In the
second phase, these small substructures are optimized to lead compound by addition or inclusion of properties of individual molecules so as to obtain a
better-optimized ligand. Different steps or doorways are present in developing lead
using fragment method, starting with library, method in identifying the interacting
fragment with protein target, structural analysis of such bound fragment, choosing
best fragment, and building the fragment into lead compound. This method largely
draws its structural and interaction information from X-ray crystallography, NMR,
surface plasma resonance, and other biophysical techniques.
The greater advantage of using the fragment-based method in drug discovery
strategies is its success in varied targets where regular high-throughput screening
fails. The targets may include large multimeric proteins, protein–protein complexes,
ubiquitin-specific proteases, etc. [131].
With a few slight variations in the workflow, the basic approach for
Fragment-Based Method (FBM) was well derived by the wake of the twenty-first
century [132–134]. The increased use of surface plasma resonance (SPR) has
boosted the fragment approach to new heights with rigorous and better fragment
binding understanding [135, 136]. In addition, many developments in implementation of other techniques such as immobilization of the protein and its reorganization by ligand using optical, NMR, mass spectrum, and other fluorescent-based
techniques [137–140] had happened.
FBM has helped in the identification and development of an FDA-approved drug
[141], and much more are in clinical trials [142]. Integration of FBM with SBDD in
identification of appropriate scaffold can significantly increase the result rate.
It should be noted that the importance and significance of small units
286
D. Velmurugan et al.