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

Authors : Adedirin Oluwaseye, Adamu Uzairu, Gideon A Shallangwa, Stephen E Abechi

Pages : 739-774

Doi:10.18596/jotcsa.304584

View : 37 | Download : 10

Publication Date : 2017-07-31

Article Type : Research Paper

Abstract :A quantitative structure–activity relationship insert ignore into journalissuearticles values(QSAR); study was performed to develop a model that relates the structures of 62 compounds, which have activity against maximal electroshock induced seizure insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(MMFF); molecular mechanics, Austin model 1 insert ignore into journalissuearticles values(AM1); semi-empirical quantum mechanical and density functional theory insert ignore into journalissuearticles values(DFT); quantum mechanical method using the Becke’s three parameter exchange functional insert ignore into journalissuearticles values(B3); hybrid with Lee, Yang and Parr correlation functional insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(GFA); algorithm was also applied to select the optimal descriptors and multiple linear regression insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(μ);, energy of the lowest unoccupied molecular orbital insert ignore into journalissuearticles values( ϵ LUMO);, polar surface area insert ignore into journalissuearticles values(PSA);, accessible surface area derived from wave function insert ignore into journalissuearticles values(WAA);, sum of the square root of square of the charge on all atom of the molecule insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(R 2 =0.937, R 2 adj =0.928, F=104.11, R 2 pred =0.929 and  Q 2 =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 insert ignore into journalissuearticles values(i.e. ethyl 4-insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(PDB code: 2KaV); and there binding affinity were found to were found to be comparable to that of phenytoin insert ignore into journalissuearticles values(a standard drug known to possess anti-MES activity);.
Keywords : MES, QSAR, GFA, Molecular docking, Kennard Stone algorithm

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