Density functional theory studies on structural properties and energies of isoniazid analogues

Abstract

The prevailing tuberculosis (TB) situation in the world demands the re-engineering and repositioning of some old drug families to achieve effective control of the spread and effects of TB. One such drug that is targeted for re-engineering is isoniazid which is also known as isonicotinohydrazide (INH). In this study, theoretical studies have been carried out to investigate twenty eight structural analogues of the isoniazid (INH) for their reactivity and some drug-likeness. The density functional theory (DFT) calculations were used to obtain the geometry of the most stable structures, HOMO, LUMO and salvation energies for the twenty eight analogues. The order of calculations Molecular mechanics followed by Semi-empirical and finally DFT minimized the chances of the structure being trapped in local minima rather that reaching the global minima. Molecular mechanics was used to prepare the input structure. The accuracy of DFT was improved by semi-empirical a calculation which checks the theoretical values against experiment. The calculations were performed on Spartan with B3LYP functional at 6-31+G* split valence basis sets. The most stable structures were used to predict the drug-likeness based on Lipinski‟s rule-of-five. In particular, the calculations involved the HOMO-LUMO energies, salvation energies and predictions of Milog P, polar surface areas, bioactivity scores, molecular weight and the number of rotatable bonds. The values obtained were compared with those of the parent molecule isoniazid. The Milog P, total polar surface area, number of hydrogen bond donors and acceptors, molecular weight, number of atoms, number of rotatable bonds were determined using the online Molinspiration software version 2011.06. The prediction of bioactivity score for drug targets (GPCR ligands, kinase inhibitors, ion channel modulators, enzymes and nuclear receptors) was also done using the online Molinspiration software version 2011.06 (www.molinspiration.com) and compared with that of the parent drug (INH). The theoretical analysis revealed that N'-[(E)-(3, 4, 5-tricyanophenyl) methylidene] pyridine-4-carbohydrazide (compound 28) is likely to be the most drug-like. It had the highest bioactivity score (-0.25) based on enzyme inhibition, norb (3), Milog P (2.13), PSA (125.73Å2), MWT (300.28) compared to the parent INH which had Milog P (-0.97), PSA, (68.013Å2 ), MWT (137.14), HOMO-LUMO energy gap of 3.9811eV bioactivity score of -0.66 and norb (1) and solvation energy of -52.12kJ/mol. Compound 28 has a HOMO-LUMO energy gap of 3.775eV indicating that this compound is likely to have low activation energy and therefore it may be more reactive, solvation energy of -68.85kJ/mol which indicates the likelihood of being soluble in water. These results pointed that compound 28 is likely to be more bioactive, flexible and is likely to have higher penetration ability through the intestinal walls than the parent drug (INH). Therefore, this class of compounds could be a good starting point to develop hit compounds which can be a lead towards developing a drug that can counter multidrug resistant tuberculosis.