In silico evaluation of 35 novel 3-hydroxy-3-pyrazolyl-1H-indolin-2-one molecules as potential neuropathic pain modulators via voltage-gated sodium channel NaV1.7

Abstrak / Ringkasan

Neuropathic pain follows nervous system dysfunction or damage, significantly affecting patients’ quality of life. The need for more effective and safer pain management has drawn attention to voltage-gated sodium channels as druggable therapeutic targets in medicinal chemistry, leading to the discovery of various compounds with pharmacological potential, among which heterocycles with pyrazole and indolone cores have stood out for their versatility. Aiming to discover new potential modulators of neuropathic pain, this research studied a series of 35 compounds with a 3-hydroxy-3-pyrazolyl-1H-indolin-2-one nucleus (molecular hybrids with pyrazole and indolone cores) by bioavailability screening, using the computational tools MedChem DesignerTM and AdmetSar 2.0, which predicted good potential to cross biological barriers and suggested theoretically favorable safety profiles. The potential use of these compounds as modulators of the voltage-gated sodium channel NaV1.7 (PDB code: 6J8G), an important molecular target in the treatment of neuropathic pain, was evaluated using molecular docking with AutoDock suite and DOCK6 software. Docking protocols were validated by redocking crystallized endogenous ligands, and results were validated using the rank-consensus approach. From those computational studies, four compounds, with the highest rank consensus values (0.52-0.59), emerged as promising candidates for experimental assays as NaV1.7 modulators. This study highlights the importance of computer-aided rational design in the discovery of new compounds with therapeutic potential in the treatment of neuropathic pain.

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