Ligand-based pharmacophore modeling for the discovery of Na[sub]V1.7 inhibitors

Piga, Martina (avtor), Lukacs, Peter (avtor), Pesti, Krisztina (avtor), Várady, György (avtor), Varga, Zoltán (avtor), Zidar, Nace (avtor), Tomašič, Tihomir (avtor)

Voltage-gated sodium channel Na$_v$1.7 is a key mediator of electrical excitability and signal transmission in peripheral nociceptors and has emerged as a highly attractive therapeutic target for the development of novel analgesic agents. However, the development of selective Na$_v$1.7 inhibitors has been characterized by significant challenges, with repeated failures in clinical trials despite encouraging preclinical data. In this study, we developed and validated a series of ligand-based pharmacophore models (LBPMs) that can be useful for the discovery of novel Na$_v$1.7 inhibitors with improved selectivity profiles. Using the VGSC database as our primary data source, we focused on sulfonamide-based inhibitors targeting the voltage-sensing domain IV (VSD-IV). Validation against active compounds and decoys demonstrated that most models achieved good discrimination performance with high areas under the curve (AUC) and strong enrichment factors. External validation using 22 inhibitors extracted from recent literature confirmed the models’ capability to identify novel Na$_v$1.7 inhibitors. Virtual screening of 3 million commercially available compounds retrieved promising hits and known inhibitors, with molecular docking studies revealing binding modes consistent with established sulfonamide-based inhibitors. Experimental validation identified one compound with measurable selectivity for Na$_v$1.7 over Na$_v$1.5, providing preliminary support for the utility of the developed virtual screening workflow. In parallel, we developed Na$_v$1.5 LBPMs to assess selectivity profiles and minimize potential cardiotoxic effects. Overall, our findings provide valuable computational tools and structural insights for the rational design of selective Na$_v$1.7 inhibitors, offering important starting points for developing analgesics with reduced off-target effects.

• Jezik: Angleški jezik
• Ključne besede: NaV1.7 inhibitors, pharmacophore model, selectivity, virtual screening, voltage-gated sodium channel
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 15 str.
• Številčenje: Vol. 40, art. 198
• PID: 20.500.12556/RUL-188594
• UDK: 615.4:54
• ISSN pri članku: 1573-4951
• DOI: 10.1007/s10822-026-00898-z
• COBISS.SI-ID: 287230979
• Datum objave v RUL: 24.09.2026

Gradivo je del revije

• Naslov: Journal of computer-aided molecular design
• Skrajšan naslov: J. comput.-aided mol. des.
• Založnik: Kluwer
• ISSN: 1573-4951
• COBISS.SI-ID: 513182745

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: zaviralci NaV1.7, farmakoforni model, selektivnost, virtualni presejalni test, napetostno odvisen natrijev kanal, farmacevtska kemija