Harnessing allosteric inhibition: prioritizing LIMK2 inhibitors for targeted cancer therapy through pharmacophore-based virtual screening and essential molecular dynamics

Vetrivel, U (2025) Harnessing allosteric inhibition: prioritizing LIMK2 inhibitors for targeted cancer therapy through pharmacophore-based virtual screening and essential molecular dynamics. Harnessing allosteric inhibition: prioritizing LIMK2 inhibitors for targeted cancer therapy through pharmacophore-based virtual screening and essential molecular dynamics, 43(3) (1129-1146).

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Abstract

The therapeutic potential of small molecule kinase inhibitors in cancer treatment is well recognized. However, achieving selectivity remains a formidable challenge, primarily due to the structural similarity of ATP binding pockets among kinases. Allosteric inhibition, which involves targeting binding pockets beyond the ATP-binding site, provides a promising alternative to overcome this challenge. In this study, a meticulous approach was implemented to prioritize type 3 inhibitors for LIMK2, employing arange of techniques including Molecular Dynamics (MD) simulations, e-pharmacophore-guided High Throughput Virtual Screening (HTVS), MM/GBSA and ADMETox analyses, Density Functional Theory(DFT) calculations, and MM/PBSA investigations. The e-pharmacophore model identifies a hypothesis featuring five essential pharmacophoric elements (RRRAH). Through virtual screening of the ZINC com-pound database, we identified only five compounds that align with all four pharmacophoric features: ZINC1044382792, ZINC1433610865, ZINC1044109145, ZINC952869440, and ZINC490621334. These compounds not only exhibit higher binding affinity but also demonstrate favorable ADME/Tox profiles. Molecular dynamics simulations underscore the stability of hydrogen bond interactions with critical cryptic LIMK2 pocket residues, Asp469 and Arg474, only for two compounds: ZINC143361086 andZINC1044382792. These compounds also exhibit superior occupancy interactions, as indicated by HOMO-LUMO analysis. Additionally, binding free energy calculations highlight the significant affinities of these two compounds when complexed with LIMK2: −83.491 ± 1.230 kJ/mol and −90.122 ± 1.248 kJ/mol for ZINC1044382792 and ZINC1433610862, respectively. Hence, this comprehensive investigation identifies ZINC1433610862 and ZINC1044382792 as prospective hits, representing promising leads for targeting LIMK2 in cancer therapeutics

Affiliation:	ICMR-National Institute for Research in Tuberculosis
Item Type:	Article
URI:	http://eprints.nirt.res.in/id/eprint/2262

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