In Silico-Guided Rational Drug Design and Synthesis of Novel 4-(Thiophen-2-yl)butanamides as Potent and Selective TRPV1 Agonists

Wedescribe an in silico-guided rational drugdesign and the synthesis of the suggested ligands, aimed at improvingthe TRPV1-ligand binding properties and the potency of N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I, a previously identified TRPV1 agonist. The docking experimentsfollowed by molecular dynamics simulations and thermodynamic analysisled the drug design toward both the introduction of a lipophilic iodineand a flat pyridine/benzene at position 5 of the thiophene nucleus.Most of the synthesized compounds showed high TRPV1 efficacy and potencyas well as selectivity. The molecular modeling analysis highlightedcrucial hydrophobic interactions between Leu547 and the iodo-thiophenenucleus, as in amide 2a, or between Phe543 and the pyridinylmoiety, as in 3a. In the biological evaluation, bothcompounds showed protective properties against oxidative stress-inducedROS formation in human keratinocytes. Additionally, while 2a showed neuroprotective effects in both neurons and rat brain slices, 3a exhibited potent antinociceptive effect in vivo..

Automated summary

We developed a rational drug design strategy and synthesized ligands to improve the binding properties and potency of a previously identified TRPV1 agonist. Molecular modeling and simulations guided the design towards introducing a lipophilic iodine and a flat pyridine/benzene at a specific position in the ligand. Most synthesized compounds showed high TRPV1 efficacy, selectivity, and protective properties against oxidative stress-induced ROS formation. The compounds also exhibited neuroprotective and antinociceptive effects in biological evaluations.