Multilayered variable selection in QSPR: A case study of modeling melting

point of Bromide Ionic Liquids

Souvik Das, Probir Kumar Ojha and Kunal Roy*

*Drug Theoretics and Cheminformatics Laboratory

Department of Pharmaceutical Technology
Jadavpur University, Kolkata-700032, India 1

What are ionic liquids?

Ionic liquids are the chemical salts characterized by the co-existence of two
oppositely charged ions held by the ionic force.
Ionic liquids (ILs) are widely used in the industry as green alternatives because of
their exceptional solvating ability and extremely low vapor pressures.
Such compounds are physically liquid with a melting point less than the boiling point
of water (i.e., 100C)
Melting point of ionic liquids is directly related to the toxicity
Cationic components of the ionic liquids are responsible for the melting point

Stark, A., Seddon, K.R., 2007. Ionic liquids, in: Seidel, A. (Ed),vol 26, Wiley, New Jersey, 836920.

Characteristics of Ionic liquids

1.
2.
3.
4.
5.

Low vapor pressure

Wide range solvating property
Liquidity over a wide temperature range
Non-flammability
High thermal stability

Pharmaceutical Industrial Applications

1.
2.
3.

For the synthesis of drugs

Facilitating drug delivery system
Pharmaceutical salts-ionic liquids (API-ILs)

Wilkes, J.S., 2002. Green Chem. 4, 7380.

Why QSPR?
m
e
l
b
o
r
P

on
i
t
u
l
o
S

Ionic liquids do not exhibit a clear melting point in the accessible

temperature range of the DSC apparatus. Many ionic liquids are
glass-transforming materials and therefore do not exhibit a clear
melting point.

Computational approach is required to predict the melting point of

ILs and their structural characteristics.

Thus arises the need for quantitative structure-property

relationship (QSPR).
Clough, Matthew T., et al. Chemical Science 6.2 (2015): 1101-1114.

What is Quantitative Structure-Property relationship (QSPR)?

It is a lead optimization process, seeking most biologically active compound of a series by

In silico method, thus systemically reduce expense, delay and manpower.

Chemical Response =f(Chemical attributes)= f(Structure, Property)

5

Objectives
1.

To reduce the difficulties facing to determine the melting point of ionic

liquids experimentally.

2.

To developed predictive QSPR models of cationic ionic liquids

3.

To validate the developed QSPR models

Materials and Methods

Dataset (376 compounds)
Descriptor calculation
Descriptor thinning (total
number of descriptor 355)

Pyridinium
bromides,
Ammonium
bromides,
Imidazolium
bromides,
Benzimidazolium
bromides

Dataset division
Modified k-medoid

Stepwise MLR for selection

of descriptors
Double cross validation using
reduced pool of descriptors

Test set
( 93compounds)

Training set
(283compounds)

GFA Spline
Best subset selection

Model
validation

Model
development

Partial least
squares
5 PLS models

Consensus model
7

Results & discussion

We have developed statistically robust QSPR models using different
chemometric tools.
We have also developed a consensus QSPR model gathering all the information
obtained from five QSPR models.

Table 1. Comparison of statistical quality and validation parameters of different models.

Final model:
Model:1
F01[C-N]
NNRS
ETA_EtaP_L
ETA_Shape_P
C-006
C-043
nArCOOR
nArCNO
F07[C-N]-2
X4Av-0.111

Best Subset selection:

Model:2
F01[C-N]
NNRS
ETA_EtaP_L
ETA_Shape_P
C-006
C-043
nCH2RX
nArCOOR
F07[C-N]-2
X4Av-0.111

Model:3
NNRS
ETA_EtaP_L
ETA_Shape_P
C-006
C-043
nCH2RX
nArCOOR
F07[C-N]-2
X4Av-0.111
5-F01[C-N]

Model:4
F01[C-N]
NNRS
ETA_EtaP_L
ETA_Shape_P
C-006
C-043
nCH2RX
nArCNO
F07[C-N]-2
X4Av-0.111

Model:5
NNRS
ETA_EtaP_L
ETA_Shape_P
C-006
C-043
nCH2RX
nArCNO
F07[C-N]-2
X4Av-0.111
5-F01[C-N]

R2= 0.612
Q2=0.584
R2pred= 0.617
Q2F2=0.615
LV= 6

R2= 0.619
Q2=0.590
R2pred= 0.614
Q2F2=0.611
LV= 8

R2= 0.619
Q2=0.589
R2pred= 0.611
Q2F2=0.609
LV= 7

R2= 0.617
Q2=0.590
R2pred= 0.610
Q2F2=0.608
LV= 7

R2= 0.617
Q2=0.590
R2pred= 0.607
Q2F2=0.604
LV= 7

Consensus model:

Q2=0.622

PLS Result:

R2pred= 0.617

MAE based criteria: Moderate

10

Mean Absolute Error (MAE) based criteria

Good predictions:
MAE (0.1 training set range) AND MAE+ 3 (0.2training set range)

Bad predictions:
MAE > (0.15 training set range ) OR MAE + 3 > (0.25 training set range)

Moderate predictions:
The predictions which do not fall under either of the above two conditions may be
considered as of moderate quality.

value denotes the standard deviation of the absolute error values for the test set data

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Descriptors

Contribution

Meaning of descriptor

F01[C-N]

+ ve

It represents the presence of a C atom linked to an electronegative atom

(such as O, N, S, P, Se, halogens) at topological distance 1

NNRS

- ve

Indicates normalized number of ring system.

ETA_EtaP_L

- ve

Indicates molecular size of compounds

ETA_Shape _P

+ ve

Related to molecular shape of the compounds

C-006

- ve

Indicates CH2RX; atom-centered fragments, where R represents any

group linked through carbon and X represents any heteroatom (O, N, S,
P, Se, and halogens)

C-043

+ ve

Represents X-CR...X, atom centered fragments , where R represents any

group linked through carbon and X represents any electronegative
atoms(O,N, S , P, Se and halogens).

nArCOOR

- ve

Indicates number of aromatic ester.

nArCNO

+ ve

Represent number of aromatic oximes.

F07[C-N]

+ ve

Represent frequency of [C-N] at topological distance 7. F07[C-N] as

well as the presence of a C atom linked to an electronegative atom (such
as O, N, S, P, Se, halogens).

X4Av

+ ve

Indicates average valence connectivity index of chi-4.

nCH2RX

+ ve

Indicates number of CH2RX where R represents any group linked

through carbon and X represents any heteroatom (O, N, S, P, Se, and
halogens)
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Contribution plot of the normalized descriptor values of

Highest & Lowest melting point ionic liquids

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Overview & Conclusions

Important Structural Features:Molecular size plays a crucial role to increase or decrease the melting point of ionic
liquids. To lower the melting point of ionic liquids, the size of the molecules should be
small.
Presence of heteroaromatic ring system, CH2RX fragments, and [O-O] atom pair at
topological distance 2 and [C-N] atom pair at topological distance 3, increases the melting
point of ionic liquids.
Absence of aromatic oximes can reduce the melting point of ionic liquids.
Presence of aromatic esters can reduce the toxicity of ionic liquids due to lowering
melting point.
All the developed QSPR models were found to be statistically robust and also shows
significant prediction quality. Thus, these models can be used for predicting the
melting points of newly designed ionic liquids.
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