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<p>Using a spectrophotometric titration approach, several fluorescent and profluorescent compounds were tested against human CYP17A1, a critical cytochrome P450 enzyme. It was found that 20α- and 20β-NBD derivatives of pregnenolone (NBD = 7-nitrobenzoxadiazole) bind to the active site of human CYP17A1 as a substrate with dissociation constants K<sub>d</sub> = 21.5 ± 3.1 μM (20α-NBD-preg) and K<sub>d</sub> = 19.8 ± 1.8 μM (20β-NBD-preg), respectively. These compounds were found not to be metabolized by the enzyme due to nonoptimal positioning of the ligands at the active site attributed to the presence of the bulky NBD group. The formation of a complex of the ligands with CYP17A1 leads to fluorescence quenching, which is stronger for the 20α isomer, possibly due to hydrogen bonding with Asn202 as found by molecular docking simulation. The identified ligands hold promise as leader compounds for the development of new molecular tools that can be used to study the mechanism of the action of human CYP17A1 and to search for high-affinity enzyme activity modulators with potential as effective new drugs.</p>

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New Human CYP17A1 Fluorescent Ligands

  • 期刊论文

  • 发表日期：

    2026年2月28日

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  • G. N. Nekrasova,
  • Ya. V. Faletrov,
  • V. M. Shkumatov,
  • Ya. V. Dichenko,
  • S. A. Usanov

摘要

Using a spectrophotometric titration approach, several fluorescent and profluorescent compounds were tested against human CYP17A1, a critical cytochrome P450 enzyme. It was found that 20α- and 20β-NBD derivatives of pregnenolone (NBD = 7-nitrobenzoxadiazole) bind to the active site of human CYP17A1 as a substrate with dissociation constants Kd = 21.5 ± 3.1 μM (20α-NBD-preg) and Kd = 19.8 ± 1.8 μM (20β-NBD-preg), respectively. These compounds were found not to be metabolized by the enzyme due to nonoptimal positioning of the ligands at the active site attributed to the presence of the bulky NBD group. The formation of a complex of the ligands with CYP17A1 leads to fluorescence quenching, which is stronger for the 20α isomer, possibly due to hydrogen bonding with Asn202 as found by molecular docking simulation. The identified ligands hold promise as leader compounds for the development of new molecular tools that can be used to study the mechanism of the action of human CYP17A1 and to search for high-affinity enzyme activity modulators with potential as effective new drugs.