DEVELOPMENT OF AN RQSA MODEL FOR THE STUDY OF INTERACTIONS BETWEEN THIENO INHIBITORS [3, 2−B] PYRROLE DERIVATIVES (TPX) AND LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1)

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, validated as a promising anti-cancer drug development target. Substantial LSD1 inhibitors design research has been reported so far.  In this work, by a rational computer-aided molecular design (CAMD) approach, a series of 23 pyrrole derivatives, LSD1 inhibitors, were docked into LSD1 active site and their affinity with the enzyme target assessed. Explains through the existing interactions between pyrrole inhibitors and LSD1 the variation of LSD1 inhibition potency substantially. The linear correlation between the experimental LSD1 inhibition biological activities() and the calculated binding affinity ) (0.1626+ 8.1632, R2 = 0.96)   explains 96% of the experimental LSD1 inhibition potency by that of the computed binding affinity. In the same way the calculated interaction energy between LSD1 and TPx, is correlated with with R2 = 0.92. The Van der Waals (VDW) component of Eint is in linear correlation with    with a coefficient of determination R_Vdw^2=0,87 while it dropped to R2 = 0.42 for the electrostatic component. Moreover, the analysis of individual contribution of the residues within the active site to the interaction energy could provide the structural information necessary to explain the inhibitory activity drop across the three classes of ligands, namely the most active, moderately active and less active ones. Then, these pyrrole derivatives with known   have been selected to build a pharmacophore (PH4) model exhibiting a linear correlation between () estimated by PH4 and the experimental inhibitory potential (). The equation of this correlation between pIC_50^exp and PH4-estimated  is   with a coefficient of determination R2=0.92. The generated 3D QSAR PH4 model is then robust for identifying new active molecules.