IN-SILICO PHARMACOPHORE MAPPING AND DOCKING STUDIES OF INDOLE/BENZOXIMIDAZOLE-5-CARBOXIMIDINE DERIVATIVES AS ANTI-CANCER AGENTS

The present research has been focused on the development of pharmacophore mapping and docking studies of indole/benzoximidazole-5-carboximidine derivatives as anti-cancer agents that can explore basic pharmacophore responsible for biological activity of structurally diverse compounds and also their binding affinity to the urokinase-type plasminogen activator (uPA). For pharmacophore mapping, a highly predictive pharmacophore based 3D-QSAR model was generated. Molecular docking experiments were carried out by means of the Glide module of the Schrodinger. A cubing receptor grid was centred around the co-crystallized ligand where the active binding site is present. The XP (extra precision) scoring function of GLIDE 6.0 was used. The scoring function of GLIDE docking program is presented in the G-score form which indicates the binding affinity of the designed compound to the receptor. A five point pharmacophore (APRRR) with one acceptor atom, one positively charged group and three aromatic rings as pharmacophore was developed. The generated best pharmacophore hypothesis yielded a statistically significant QSAR model, with a correlation coefficient of R2 = 0.8548 for training set molecules. The same sets of molecules were docked with urokinase-type plasminogen activator as target protein. The Gscore of the ligand 25 was found to be -11.89 as comparable with the G-score of reference drug (132: 6-CHLORO-2-(2-HYDROXY-BIPHENYL-3-YL)-1H-INDOLE-5-CARBOXAMIDINE) i.e.-11.626. The present study aimed to develop ligand based pharmacophore hypothesis and an interaction pattern by docking. Both studies rendered significant information which highlights important binding features of uPA inhibitors which can be utilized further in the successful designing of novel highly active analogues against uPA.