speed in the case of protein kinase MD is around 500 ns/24 h/kinase, and several
simulations (typically more than 10) are run simultaneously. This equals to around
5 microseconds produced MD data within 24 h. Together with ever-continuing work
on new protein-specific and general force fields [32–36], this has allowed researchers
to carry out long enough simulations with good accuracy for the kinase inhibitor
complex. Naturally, currently available force fields are far from perfect, and there are
several attempts to include polarizability and proton transfers within classical force
fields [37, 38]. However, the current status of force field methods is good enough to
allow high-quality simulations which are reproducing empirical data within a reasonable error margin.
Force field development is not the only reason why MD simulations are nowadays useful in drug design. Another breakthrough is a method called Markov State
Models (MSMs). MSMs are kinetic models of the process under study, usually
based on MD trajectory data. The aim of the MSM approach is to build a simplified
model, easy to understand and simple enough that new insight can be gained. MSM
is a coarse-grained representation of the more detailed molecular trajectories for
quantitative comparisons [30]. The method builds a model with individual (metastable) states and detects how often conversion from one state to another is happening. MSMs often have thousands of states or even more. The critical factor is the
transition from one state to another, and with faster transitions, shorter simulations
are needed to construct an MSM. As Pande et al. explain in their excellent review,
the specific challenges for building an MSM can be broken down into (1) how does
one define states in a kinetically meaningful scheme and (2) how can one transition
the matrix in an efficient manner. If done properly, the MSM will yield both
a detailed enough model about the phenomenon under study and at the same time
a confirmation that the given simulation time is long enough to construct such a
model [30].
Kinase inhibitor design is a typical structure-based design process, utilizing
structural biology and X-ray structures. However, several MD simulation studies
have recently been able to reproduce most, if not all, relevant protein conformations
within selected protein kinase families [31, 39, 40]. In addition, similar studies have
detected previously unknown inactive kinase structures, which have either been later
validated by structural biology approaches or confirmed by X-ray structure in related
kinases. Sultan, Kiss, and Pande [41] used an accelerated molecular dynamics
(AMD) to study seven Src kinase structures simultaneously. They also utilized an
extension of the MSM method which allowed the authors to compare MD trajectories of seven Src kinases, namely, Fyn, Lyn, Lck, Hck, Fgr, Yes, and Bl kinase. The
total length of AMD simulations exceeded several milliseconds. Results indicated
that the kinase active state of the seven Src kinases is typically within 1–2 kcal/mol
of the inactive conformation. In addition, kinase activation is slower than deactivation. The active-inactive transitions require several metastable intermediates, and
potentially those conformations can be targeted by specific inhibitors.
Although docking is carried out in vacuum, water molecules can be considered
during the docking procedure. Protein-ligand solvation and desolvation are the major
sources of binding energy during protein-ligand binding [42]. Indirectly, water is
32
A. Poso
simulations (typically more than 10) are run simultaneously. This equals to around
5 microseconds produced MD data within 24 h. Together with ever-continuing work
on new protein-specific and general force fields [32–36], this has allowed researchers
to carry out long enough simulations with good accuracy for the kinase inhibitor
complex. Naturally, currently available force fields are far from perfect, and there are
several attempts to include polarizability and proton transfers within classical force
fields [37, 38]. However, the current status of force field methods is good enough to
allow high-quality simulations which are reproducing empirical data within a reasonable error margin.
Force field development is not the only reason why MD simulations are nowadays useful in drug design. Another breakthrough is a method called Markov State
Models (MSMs). MSMs are kinetic models of the process under study, usually
based on MD trajectory data. The aim of the MSM approach is to build a simplified
model, easy to understand and simple enough that new insight can be gained. MSM
is a coarse-grained representation of the more detailed molecular trajectories for
quantitative comparisons [30]. The method builds a model with individual (metastable) states and detects how often conversion from one state to another is happening. MSMs often have thousands of states or even more. The critical factor is the
transition from one state to another, and with faster transitions, shorter simulations
are needed to construct an MSM. As Pande et al. explain in their excellent review,
the specific challenges for building an MSM can be broken down into (1) how does
one define states in a kinetically meaningful scheme and (2) how can one transition
the matrix in an efficient manner. If done properly, the MSM will yield both
a detailed enough model about the phenomenon under study and at the same time
a confirmation that the given simulation time is long enough to construct such a
model [30].
Kinase inhibitor design is a typical structure-based design process, utilizing
structural biology and X-ray structures. However, several MD simulation studies
have recently been able to reproduce most, if not all, relevant protein conformations
within selected protein kinase families [31, 39, 40]. In addition, similar studies have
detected previously unknown inactive kinase structures, which have either been later
validated by structural biology approaches or confirmed by X-ray structure in related
kinases. Sultan, Kiss, and Pande [41] used an accelerated molecular dynamics
(AMD) to study seven Src kinase structures simultaneously. They also utilized an
extension of the MSM method which allowed the authors to compare MD trajectories of seven Src kinases, namely, Fyn, Lyn, Lck, Hck, Fgr, Yes, and Bl kinase. The
total length of AMD simulations exceeded several milliseconds. Results indicated
that the kinase active state of the seven Src kinases is typically within 1–2 kcal/mol
of the inactive conformation. In addition, kinase activation is slower than deactivation. The active-inactive transitions require several metastable intermediates, and
potentially those conformations can be targeted by specific inhibitors.
Although docking is carried out in vacuum, water molecules can be considered
during the docking procedure. Protein-ligand solvation and desolvation are the major
sources of binding energy during protein-ligand binding [42]. Indirectly, water is
32
A. Poso