A novel QSAR model for designing, evaluating, and predicting the antiMES activity of new 1H-pyrazole-5-carboxylic acid derivatives

Year 2017, Volume: 4 Issue: 3, 739 - 774, 31.07.2017

Adedirin Oluwaseye Adamu Uzairu Gideon A. Shallangwa Stephen E. Abechi

https://doi.org/10.18596/jotcsa.304584

Cited By: 5

Abstract

A quantitative
structure–activity relationship (QSAR) study was performed to develop a model
that relates the structures of 62 compounds, which have activity against
maximal electroshock induced seizure (MES), with their anti-MES activity.
Molecular structures of the compounds were geometrically optimized and
energetically minimized using a combination of modified Merck force field
(MMFF) molecular mechanics, Austin model 1 (AM1) semi-empirical quantum
mechanical and density functional theory (DFT) quantum mechanical method using
the Becke’s three parameter exchange functional (B3) hybrid with Lee, Yang and
Parr correlation functional (LYP) and basis set of the double zeta split
valence plus polarization quality 6-31G** i.e. B3LYP/6-31G**. Theoretically
derived descriptors were obtained from the optimized structures, a genetic
function approximation (GFA) algorithm was also applied to select the optimal
descriptors and multiple linear regression (MLR) was used to establish a relationship
between the anti-MES activity of the compounds and the optimal molecular
descriptors. A six-parametric equation containing dipole moment (μ), energy of
the lowest unoccupied molecular orbital (ϵLUMO), polar surface area (PSA),
accessible surface area derived from wave function (WAA), sum of the square
root of square of the charge on all atom of the molecule (QA) and sum of the
square root of square of the charge on all fluorine atom in the molecule was
obtained as the QSAR model in the present study with good statistical qualities
(R²=0.937, R²_adj=0.928, F=104.11, R²_pred=0.929
and  Q²=0.913). The QSAR model
was used to study estimate the anti-MES activities of 1H-pyrazole-5-carboxylic acid derivatives not yet synthesized. 10
out of the 101 screened compounds had improved anti-MES activity when compared
to the template (i.e. ethyl
4-(4-chlorophenyl)-3-morpholino-1H-pyrrole-2-carboxylate, which is compound
number 61 in the dataset) used to design the 101 derivatives. These 10
compounds were docked with voltage-gated sodium channel (PDB code: 2KaV) and
there binding affinity were found to were found to be comparable to that of
phenytoin (a standard drug known to possess anti-MES activity).

Keywords

: MES, QSAR, GFA, Molecular docking, Kennard-Stone algorithm

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