Docking studies and molecular dynamics simulation of triazole benzene sulfonamide derivatives with human carbonic...

Carbonic anhydrase IX has been used as a hypoxia endogenous marker in a range of solid tumors including renal cell, lung, bladder and tumors of the head and neck. α-CA IX isozyme is over-expressive in hypoxic environment which becomes an attractive target for the design of inhibitors' targeting cancer particularly, tumor progression and invasion. In the process of designing new leads for the inhibition of tumor-associated hCA IX, the best triazole benzene sulfonamide derivatives were obtained from the QSAR model published in the research paper as cited. The statistically validated QSAR model was utilized for bioactivity prediction of novel leads. Further the designed molecules having good scores were subjected to molecular docking studies and molecular dynamic simulation studies. Designed compounds 1, 2, 20, 24 and 27 have shown predicted bioactivity of 9.13, 9.65, 10.05, 10.03 and 10.104 logarithmic units respectively using QSAR model 2. The low energy conformations of the above compounds exhibited good Autodock binding energy scores (-8.1, -8.2, -8.1, -8.3 and -9.2 K cal mol^-1) and interactions with Gln92, Thr200, Asn66 and His68. Desmond's molecular dynamics simulations studies for 100 ns of compound 27 compared to reference SLC0111 provided useful structural insights of human carbonic anhydrase IX inhibition. Compound 27 with new chemical structure displayed both hydrophobic and hydrophilic stable interactions in the active site. RMSD, RMSF, RoG, H-bond and SASA analysis confirmed the stable binding of compound 27 with 5FL4 structure. In addition, MM-PBSA and MM-GBSA also affirm the docking results. We propose the designed compound 27 (predicted Ki = ∼0.07 nM) as the best theoretical lead which may further be experimentally studied for selective inhibition.