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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

. (Ed). Wiley.e. A. 2007. 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. K.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. 836–920.R. in: Seidel. New Jersey.vol 26.. 2 . Ionic liquids. A. Seddon. 100°C) Melting point of ionic liquids is directly related to the toxicity Cationic components of the ionic liquids are responsible for the melting point Stark.

5. 4. 73–80. Low vapor pressure Wide range solvating property Liquidity over a wide temperature range Non-flammability High thermal stability Pharmaceutical Industrial Applications 1. J. 4. 2002.Characteristics of Ionic liquids 1.S. 3 . 2. 3.. For the synthesis of drugs Facilitating drug delivery system Pharmaceutical salts-ionic liquids (API-ILs) Wilkes. 2. 3. Green Chem.

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). Matthew T. et al. Clough. 4 .. Chemical Science 6.2 (2015): 1101-1114.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.

seeking most biologically active compound of a series by In silico method. Chemical Response =f(Chemical attributes)= f(Structure.What is Quantitative Structure-Property relationship (QSPR)? P It is a lead optimization process. thus systemically reduce expense. Property) 5 . delay and manpower.

To developed predictive QSPR models of cationic ionic liquids 3.Objectives 1. 2. To validate the developed QSPR models 6 . To reduce the difficulties facing to determine the melting point of ionic liquids experimentally.

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 .Materials and Methods Dataset (376 compounds) Descriptor calculation Descriptor thinning (total number of descriptor 355) Pyridinium bromides. Ammonium bromides. Imidazolium bromides.

8 .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.

589 R2pred= 0.611 Q2F2=0.617 Q2=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-0.607 Q2F2=0.614 Q2F2=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-0.615 LV= 6 R2= 0.111 5-F01[C-N] R2= 0.590 R2pred= 0.584 R2pred= 0.610 Q2F2=0.Table 1.111 Model:5 NNRS ETA_EtaP_L ETA_Shape_P C-006 C-043 nCH2RX nArCNO F07[C-N]-2 X4Av-0.590 R2pred= 0.111 Model:3 NNRS ETA_EtaP_L ETA_Shape_P C-006 C-043 nCH2RX nArCOOR F07[C-N]-2 X4Av-0.608 LV= 7 R2= 0. Comparison of statistical quality and validation parameters of different models.609 LV= 7 R2= 0.604 LV= 7 Consensus model: Q2=0. 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-0.619 Q2=0.617 Q2=0.619 Q2=0.617 Q2F2=0.590 R2pred= 0.612 Q2=0.622 PLS Result: R2pred= 0.617 MAE based criteria: Moderate 9 .611 LV= 8 R2= 0.

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σ value denotes the standard deviation of the absolute error values for the test set data 11 .1 ×training set range) AND MAE+ 3 ×σ ≤ (0.Mean Absolute Error (MAE) based criteria Good predictions: MAE ≤ (0.2×training set range) Bad predictions: MAE > (0.15 training set range ) OR MAE + 3 × σ > (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.

nCH2RX + ve Indicates number of CH2RX where R represents any group linked through carbon and X represents any heteroatom (O. F07[C-N] + ve Represent frequency of [C-N] at topological distance 7. N. where R represents any group linked through carbon and X represents any heteroatom (O. where R represents any group linked through carbon and X represents any electronegative atoms(O. S. N. Se.. S. nArCNO + ve Represent number of aromatic oximes. P. P. S. P. S .N.X. and halogens) 12 .ve Indicates number of aromatic ester. Se. P. N. nArCOOR . atom-centered fragments.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. and halogens) C-043 + ve Represents X-CR.ve Indicates normalized number of ring system. Se. P..ve Indicates CH2RX. Se. X4Av + ve Indicates average valence connectivity index of chi-4. halogens) at topological distance 1 NNRS . Se and halogens). atom centered fragments . S. halogens). F07[C-N] as well as the presence of a C atom linked to an electronegative atom (such as O. N. ETA_EtaP_L .ve Indicates molecular size of compounds ETA_Shape _P + ve Related to molecular shape of the compounds C-006 .

Contribution plot of the normalized descriptor values of Highest & Lowest melting point ionic liquids 13 .

increases the melting point of ionic liquids. 14 . Presence of aromatic esters can reduce the toxicity of ionic liquids due to lowering melting point. and [O-O] atom pair at topological distance 2 and [C-N] atom pair at topological distance 3. the size of the molecules should be small. Thus. All the developed QSPR models were found to be statistically robust and also shows significant prediction quality. To lower the melting point of ionic liquids.Overview & Conclusions Important Structural Features:Molecular size plays a crucial role to increase or decrease the melting point of ionic liquids. CH2RX fragments.  Absence of aromatic oximes can reduce the melting point of ionic liquids. Presence of heteroaromatic ring system. these models can be used for predicting the melting points of newly designed ionic liquids.

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