Molecular docking-based virtual screening, molecular dynamic simulation, and 3-D QSAR modeling of some...

Lymphatic filariasis and onchocerciasis are common filarial diseases caused by filarial worms, which co-habit symbiotically with the Wolbachia organism. One good treatment method seeks Wolbachia as a drug target. Here, a computer-aided molecular docking screening and 3-D QSAR modeling were conducted on a series of Fifty-two (52) pyrazolopyrimidine derivatives against four Wolbachia receptors, including a pharmacokinetics study and Molecular Dynamic (MD) investigation, to find a more potent anti-filarial drug. The DFT approach (B3LYP with 6-31G** option) was used for the structural optimization. Five ligand-protein interaction pairs with the highest binding affinities were identified in the order; 23_7ESX (-10.2 kcal/mol) > 14_6EEZ (- 9.0) > 29_3F4R (- 8.0) > 26_6W9O (- 7.7) ≈ doxycycline_7ESX (- 7.7), with good pharmacological interaction profiles. The built 3-D QSAR model satisfied the requirement of a good model with R² = 0.9425, Q² _LOO = 0.5019, SDEC = 0.1446, and F test = 98.282. The selected molecules (14, 23, 26, and 29) perfectly obeyed Lipinski's RO5 for oral bio-availability, and showed excellent ADMET properties, except 14 with positive AMES toxicity. The result of the MD simulation showed the great stability associated with the binding of 23 onto 7ESX's binding pocket with an estimated binding free energy (MM/GBSA) of - 60.6552 kcal/mol. Therefore, 23 could be recommended as a potential anti-filarial drug molecule, and/or template for the design of more prominent inhibitors.

The online version contains supplementary material available at 10.1007/s40203-022-00136-y.