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Quantitative structure–activity relationship (QSAR) techniques, especially those that possess three-di-
mensional attributes, such as the comparative molecular field analysis (CoMFA), are frequently used in mod-
ern-day drug design and other related research domains. However, the requirement for accurate alignment of
compounds in CoMFA increases the difficulties encountered in its use. This has led to the development of several
techniques—such as VolSurf, Grid-independent descriptors (GRIND), and Anchor-GRIND—which do not
require such an alignment. We propose a technique to construct the prediction model that uses mo-lecular
interaction field grid potentials as inputs to convolutional neural network. The proposed model has been found
to demonstrate higher accuracy compared to the conventional descriptor-based QSAR models as well as
Anchor-GRIND techniques. In addition, the method is target independent, and is capable of provid-ing useful
information regarding the importance of individual atoms constituting the compounds contained in the chemical
dataset used in the proposed analysis. In view of these advantages, the proposed technique is expected to find
wide applications in future drug-design operations.
Key words activity prediction; molecular interaction field; deep learning; three-dimensional quantitative
structure–activity relationship
l ( x > l)
y = x (l ≥ x ≥ −l) (4)
Fig. 2. Overview of Data Rotation − l ( − l > x)
An initial structure of an example molecule is shown on the top. After multiply-ing y =tanh(l × x) (5)
the coordinates of its atoms by a random rotation matrix, a new set of coordi-nates
showing a rotated structure (e.g., the structure shown on the lower left) can be
obtained. By changing the rotation matrix 100 times, 100 rotated structures of the x−μ
molecule can be obtained.
y= σ (6)
*7
1.07Rij* 7 1.12Rij −2
Evdwij =εij
7 7
* *
Rij + 0.07Rij Rij +0.12Rij
qi q j
EQij =332.0716 D ( Rij +δ)
Scaling Grid potentials calculated in the above step can-not
directly be used as inputs to CNN because the computa-tional
grid-potential domain covers the entire range from −∞
(1) Learning The network architecture employed in this study is depicted in
Fig. 4, and was constructed with reference to the Visual Geometry Group
(VGG) model10) using mxnet-0.10.0.16)
Weight initialization was performed in a manner similar to the
one previously reported by Glorot and Bengio17) Batch size and
epoch were set to 100 and 500,
respectively. The softmax cross-entropy
error function was employed to account for
losses along with use of the Adam
optimization algorithm.18) Other hyper
parameters were determined using the
method described in the next section.
Tuned hyper parameters, in Fig.
4, are indicated in italics. The input MIF
was first prepared using the ‘preparation
type’ and ‘preparation range’ hyper
parameters. Convolutional layers were then
added a number of times equal to the value
of the layers parameter. The density layers
are then repeated a number of times equal
to the value of the ‘densely connected
layers’ parameter. Finally, the soft-max
cross-entropy loss function is applied.
Hyper-Parameter Tuning In order to
obtain optimum values for hyper
parameters, 29 compounds, corresponding
to 10% of the training set, were randomly
selected as a valida-tion set and a random
search operation was performed. Each
hyper parameter listed in Table 2 was
randomly chosen, and subsequent learning
was performed on the training set. This
procedure was performed for 100 different
hyper-parameter patterns, and the
parameter demonstrating highest accuracy
was selected for the validation test.
Prediction and Model Evaluation One
prediction was obtained from each of the
hundred rotated structures cor-responding
to each compound, and the final prediction
result was derived on the basis of majority
vote with reference to the 10-crop testing.9)
Figure 5 depicts a schematic of this op-
(2)
eration, which is hereinafter referred to as
100-rotate testing (100-RT). The prediction
accuracy of the model was evaluated by the
test set.
estimating the prediction probability of a compound when a QSAR with 2D Descriptors For the purpose of com-parison,
certain atom is not present. In the proposed study, each atom random forest (RF)19) and logistic regression (LR)20) models
constituting the compound to be inspected was omitted one at a using 2D descriptors exclusively were constructed to form a
time, and the corresponding grid potential was calculated. The baseline case. The Mordred -0.6.0 package21) was used for
100-RT operation was then performed for each omitted atom. descriptor calculation while the scikit-learn-0.19.022) pack-age
The decline of the predictive probability between the initial and was used for model construction. Hyper parameters were once
atom-omitted structures indicates the importance of the omitted again determined through a random search of 100 points in the
atom. Finally, all the atoms demonstrating high importance were ranges listed in Table 3. For evaluating hyper param-eters,
highlighted according to the calculated atomic importance. validation accuracy determined using the 10-fold cross-
Figure 6 shows an illustration of the above process. validation (10-CV) technique was used.
430 Chem. Pharm. Bull. Vol. 67, No. 5 (2019)
Table 2. Tuned Hyper Parameters and Their Corresponding Range Results and Discussion
The proposed method was developed to investigate the
Hyper parameter Range feasibility of CNN—to which MIF potential grids serve as in-
Convolutional layers 4,6 puts—as a useful 3D-QSAR tool in contemporary drug design
Initialchannel 2 1.0 ,5.0 and related medical research. To demonstrate the applicability
Densely connected layers 0,3 of the proposed method, this section compares its prediction
Densely connected layer width 2 7.0 ,11.0 capability against that of conventional descriptor-based models
Preparation type tanh or clip employing 2D descriptors and the previously reported Anchor-
Preparation range 0.05,1.0
prepare type =tanh GRIND model. Subsequently, the contribution of hyper pa-
0.05,100.0 prepare type =clip rameters involved in CNN is discussed. Lastly, the usefulness of
Ul, u represents the value sampled from the uniformly distributed random number in
the proposed analysis procedure to highlight the importance of
the range [l, u) (continuous distribution if l and u are decimal numbers, and discrete individual atoms of a compound in activity prediction is
distribution if they are integers). discussed.
Table 3. Tuned Hyper Parameters and Their Corresponding Range in 2D Descriptor Models
Test
Validation
Model accuracy Balanced
Accuracy
(%) accuracy F1 score
(%)
(%)
Proposed 96.4 91.7 91.0 0.933
RF 94.1 85.5 83.7 0.885
LR 94.5 90.3 89.6 0.921
1 1FJS 0.11
2 1NFY 1.3
3 1LQD 9
* All the three ligands are in active class.
Comparison with Other Methods Table 4 lists hyper Fig. 7. Inspection of Importance of Individual Atoms in a Compound
parameters of the proposed, RF, and LR models along with The atomic importance of ligands 1, 2, and 3 are shown here. Circle indicates
corresponding accuracies of their respective validation (hold out important atoms according to the calculation of atomic importance in a scale that varies
validation of the propped method and 10-CV technique for RF from colorless to red. A rescaled mapping of atomic importance of ligand 3 is also
shown as 3 here. (Color figure can be accessed in the online version.)
and LR methods) and test sets.
As seen in Table 4, the proposed method demonstrates a test-
set accuracy of 91.7%, which is higher compared to the Anchor- proposed model, is depicted in Fig. 7.
GRIND (88%) and baseline models employing 2D de-scriptors Each molecule is highlighted based on the significance of its
(85.5% for RF and 90.3% for LR). Balanced accuracy and F1 constituent atoms, which is expressed by means of a color scale
score of the proposed model are also higher than those of 2D that varies from colorless to red with increase in sig-nificance.
descriptor models. By directly performing the predic-tion for all Since the activity of Ligand 3 is close to the active/ inactive
14500 rotated structures in the test set without invoking the 100- threshold and it is difficult to distinguish between active and
RT operation, the accuracy was found to be 90.2%, thereby inactive, most atoms in Ligand 3 are highlighted. Thus, the
suggesting that the 100-RT operation serves to achieve an rescaled image (3 ) is also shown.
improvement of roughly 1.5 percentage points in prediction The amidine substructure of benzimidazole in Ligands 1 and
accuracy. 3 was highlighted to be important but was not in Ligand 2 was
Explanation of the Model Explanation of QSAR models is not. To identify reason of this discrepancy, X-ray co-crystal
generally difficult. For the purpose of drug design, however, an structures of Ligands 1–3 (PDBID: 1FJS, 1NFY, and 1LQD) are
explanation of the constructed model is necessary. As pre- superimposed and compared (Fig. 8). Ligands 1–3 are colored
viously mentioned, the proposed model is capable of providing in red, green, and cyan, respectively. Residues demonstrating
information regarding the importance of individual atoms in a major interaction with compounds are also shown. Compared
compound by comparing prediction probability obtained via with Ligands 1 and 3, Ligand 2 is clearly showing different
omission of individual atoms from the compound one-at-a-time. binding mode in the co-crystal structure. For Ligand 2, instead
For the dataset considered in this study, three co- of benzamidine, chlorobenzene is posi-tioned in the active site
crystallographic structures of compounds with receptor Factor and one of nitrogen of benzamidine in Ligand 2 forms hydrogen
Xa were reported to the Protein Data Bank (PDB) (Table 5). All bond with Glu97. In Fig. 7, chloro group in Ligand 2 is strongly
the three ligands are in active class. An illustration of the atomic highlighted and one of nitrogen of benzamidine is highlighted.
importance of these compounds, as determined by the The results consistent with
432 Chem. Pharm. Bull. Vol. 67, No. 5 (2019)
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