conformer and design inhibitors accordingly. If inhibitors can be
designed based on the structure of the preferred conformer, these
inhibitors would bind the preferred conformer more selectively.
Binding of inhibitor would then shift the conformational equilibrium in favor of that conformer, increasing drug binding to the
target [12]. In summary, incorporation of protein motion and
conformation studies represents a great opportunity for drug discovery design. Despite such research being ill-suited to highthroughput methods, it may be necessary because we may be overlooking a realm of novel drug design possibilities.
7 Conclusion
In this work, DHFR was used as a case study for the methods and
approaches to study the role of conformational selection and
motions in ligand binding, the effects of distal mutations on the
conformational motions of DHFR on inhibitor binding, and the
potential implications these findings may have on drug discovery
and design. The studies as a whole show that conformational
motions play a crucial role in ligand binding during the catalytic
cycle and binding of inhibitor molecules such as MTX, TMP, and
PYR. Distal mutations affect ligand binding and the conformational motions associated with inhibitor binding. Novel methods
are needed to investigate the hypothesis that proteins exist as a
conformational ensemble in a state of dynamic equilibrium and a
network of amino acids located both near and away from the active
site are required for protein function. Distal mutations most likely
exert their effects by modulating conformational motions indirectly
through this network of amino acids that make up the global
protein dynamics and these effects can only in part be captured
through enzyme kinetics and NMR. Finally, these observations may
have useful implications in drug design. Conformational changes
associated with inhibitor binding were shown to be inhibitor specific, which implies that drug action may be broader than we
originally thought. Inhibitors may exert their effects through disrupting functional protein dynamics instead of simply blocking
substrate binding to the active site. Therefore, methods to study
the conformational motions that may be potential “drug targets”
can reveal opportunities for the design of better and more selective
inhibitors.
References
1. Vogt AD, Di Cera E (2012) Conformational
selection or induced fit? A critical appraisal of
the kinetic mechanism. Biochemistry 51
(30):5894–5902
2. Vogt AD, Pozzi N, Chen Z, Di Cera E (2014)
Essential role of conformational selection in
ligand binding. Biophys Chem 186:13–21
3. Csermely P, Palotai R, Nussinov R (2010)
Induced fit, conformational selection and
214
Melanie Goldstein and Nina M. Goodey
designed based on the structure of the preferred conformer, these
inhibitors would bind the preferred conformer more selectively.
Binding of inhibitor would then shift the conformational equilibrium in favor of that conformer, increasing drug binding to the
target [12]. In summary, incorporation of protein motion and
conformation studies represents a great opportunity for drug discovery design. Despite such research being ill-suited to highthroughput methods, it may be necessary because we may be overlooking a realm of novel drug design possibilities.
7 Conclusion
In this work, DHFR was used as a case study for the methods and
approaches to study the role of conformational selection and
motions in ligand binding, the effects of distal mutations on the
conformational motions of DHFR on inhibitor binding, and the
potential implications these findings may have on drug discovery
and design. The studies as a whole show that conformational
motions play a crucial role in ligand binding during the catalytic
cycle and binding of inhibitor molecules such as MTX, TMP, and
PYR. Distal mutations affect ligand binding and the conformational motions associated with inhibitor binding. Novel methods
are needed to investigate the hypothesis that proteins exist as a
conformational ensemble in a state of dynamic equilibrium and a
network of amino acids located both near and away from the active
site are required for protein function. Distal mutations most likely
exert their effects by modulating conformational motions indirectly
through this network of amino acids that make up the global
protein dynamics and these effects can only in part be captured
through enzyme kinetics and NMR. Finally, these observations may
have useful implications in drug design. Conformational changes
associated with inhibitor binding were shown to be inhibitor specific, which implies that drug action may be broader than we
originally thought. Inhibitors may exert their effects through disrupting functional protein dynamics instead of simply blocking
substrate binding to the active site. Therefore, methods to study
the conformational motions that may be potential “drug targets”
can reveal opportunities for the design of better and more selective
inhibitors.
References
1. Vogt AD, Di Cera E (2012) Conformational
selection or induced fit? A critical appraisal of
the kinetic mechanism. Biochemistry 51
(30):5894–5902
2. Vogt AD, Pozzi N, Chen Z, Di Cera E (2014)
Essential role of conformational selection in
ligand binding. Biophys Chem 186:13–21
3. Csermely P, Palotai R, Nussinov R (2010)
Induced fit, conformational selection and
214
Melanie Goldstein and Nina M. Goodey