below an IC 50 value of 100 µM and compound AN-648/41665045 showed an IC 50
value of 9.35 µM. Notably, none of these compounds has previously been reported
as an inhibitor for RNase H [48]. (Fig. 4).
5.4 QM Fragmentation Approach
In this approach, whole protein is fragmented into individual amino acids, and the
fragment-wise interaction energies with ligand are calculated and added together to
get the total interaction energies as in the equation below. Since the whole protein is
broken into individual fragments, the size of the protein is not a problem any more
and a high-level electronic structure theory such as Møller–Plesset perturbation
theory or coupled cluster method that accounts for electronic correlation explicitly
can be used to compute the subsystem interaction energies [49].
DE ¼
X n
i¼1
DE ðAiÀligandÞ
ð9Þ
where Ai is the ith amino acid in a receptor, n is the total number of amino acids,
and Ai-ligand refers to the ith residue–ligand complex. The ΔE is interaction energy
between the ith residue and the ligand, which itself is computed as below:
DE AiÀligand ¼ E AiÀligand À E Ai À E ligand
ð10Þ
The amino acids are cut along the peptide bond and capped either with hydrogens or with other functional groups to mimic protein-like environment around the
residue. When the hydrogen atoms are employed as capping atom, then the above
equation for the calculation of interaction energy is sufficient. However, it is
appropriate to use –NHCH 3 and –CO–CH 3 as capping groups for either side of the
amino acids. Moreover, the additional contributions to the interaction energies due
to these capping residues should be removed as below:
E pÀL ¼
X NÀ2
k¼1
E F k ÀL À
X NÀ3
k¼1
E CC k ÀL À
X NÀ2
k¼1
E Fk þ
X NÀ3
k¼1
E CC k À E L
ð11Þ
In this case, the interactions are due to two molecular entities (a ligand and an
amino acid) at a time and so we completely ignore the three-body contributions to
the total interaction energies. In other words, this is similar to making an
assumption that interaction between an amino acid and the ligand is not modulated
by the presence of the neighbouring amino acids (or fragments). However, by doing
additional calculations for estimating the interaction energies of dipeptide (or in
units of two amino acids) and ligand at a time, such three-body contributions can be
included. The expression for interaction energy is now a bit more complicated and
236
N. A. Murugan et al.
value of 9.35 µM. Notably, none of these compounds has previously been reported
as an inhibitor for RNase H [48]. (Fig. 4).
5.4 QM Fragmentation Approach
In this approach, whole protein is fragmented into individual amino acids, and the
fragment-wise interaction energies with ligand are calculated and added together to
get the total interaction energies as in the equation below. Since the whole protein is
broken into individual fragments, the size of the protein is not a problem any more
and a high-level electronic structure theory such as Møller–Plesset perturbation
theory or coupled cluster method that accounts for electronic correlation explicitly
can be used to compute the subsystem interaction energies [49].
DE ¼
X n
i¼1
DE ðAiÀligandÞ
ð9Þ
where Ai is the ith amino acid in a receptor, n is the total number of amino acids,
and Ai-ligand refers to the ith residue–ligand complex. The ΔE is interaction energy
between the ith residue and the ligand, which itself is computed as below:
DE AiÀligand ¼ E AiÀligand À E Ai À E ligand
ð10Þ
The amino acids are cut along the peptide bond and capped either with hydrogens or with other functional groups to mimic protein-like environment around the
residue. When the hydrogen atoms are employed as capping atom, then the above
equation for the calculation of interaction energy is sufficient. However, it is
appropriate to use –NHCH 3 and –CO–CH 3 as capping groups for either side of the
amino acids. Moreover, the additional contributions to the interaction energies due
to these capping residues should be removed as below:
E pÀL ¼
X NÀ2
k¼1
E F k ÀL À
X NÀ3
k¼1
E CC k ÀL À
X NÀ2
k¼1
E Fk þ
X NÀ3
k¼1
E CC k À E L
ð11Þ
In this case, the interactions are due to two molecular entities (a ligand and an
amino acid) at a time and so we completely ignore the three-body contributions to
the total interaction energies. In other words, this is similar to making an
assumption that interaction between an amino acid and the ligand is not modulated
by the presence of the neighbouring amino acids (or fragments). However, by doing
additional calculations for estimating the interaction energies of dipeptide (or in
units of two amino acids) and ligand at a time, such three-body contributions can be
included. The expression for interaction energy is now a bit more complicated and
236
N. A. Murugan et al.