Targeting the Catalytically Important Residues Based on Combined Atom Based Qsar, Pharmacophore Development, DFT and Molecular Dynamics Studies Using Thiamine Analogs Against Human Transketolase Like Protein 1 (TKTL1)

Abstract

Transketolase like protein 1 (TKTL1), is a connecting link between Glycolysis and Pentose Phosphate Pathway hatching to be potential drug target for inhibiting the ATP energy synthesis in cancerous cells. TKTL1 protein consists of potential active site residues His30, His46, Ser49, Glu128, Lys84, Lys218 playing a role in protonation and Schiff base reaction for the catalytic activity. Several inhibitors have been proposed but could not be succeed in pre-clinical and clinical studies. In this study, thiamine analogs were rationalized to identify novel compounds which could deform the protonation and Schiff base reaction with the active site residues. Five point pharmacophore hypotheses AADHR was highly predictive and prolific resulting in pool of compounds with high binding affinity. The hypothesis was statistically significant with coefficient of correlation r2 = 0.73 and cross validation correlation coefficient q2= 0.55. External validation result displays, significance of the model with r2 (o) of 0.99 and r2 (m) of 0.51. Based on the hypothesis, the compounds were screened using different databases and quantum mechanical calculations were applied to top five screened compounds for the chemical reaction of the compounds. The stability of the complexes was analyzed by MDS studies. This present study signifying the potential of novel compounds which could be effectively inhibit the activity of TKTL1 protein in cancerous cells.

Keywords: Glycolysis, Pentose phosphate pathway, TKTL1 protein, DFT, Thiamine analogues