Structure-based discovery of potent SMO inhibitors guided by MM/GBSA binding free energies in hedgehog-driven cancers

The Hedgehog (Hh) signaling pathway, crucial for embryonic development and tissue homeostasis, is frequently dysregulated in cancers, making its core component, the Smoothened (SMO) receptor, a prime therapeutic target. This study employed an integrative computational strategy to identify novel SMO inhibitors. Virtual screening of the ZINC database highlighted ZINC000299767263 (ZINC7263) as a top candidate, exhibiting a Glide score of -10.86 and MM/GBSA binding energy of -65.3 kJ/mol, comparable to the FDA-approved inhibitor Vismodegib. Molecular docking revealed critical interactions with SMO residues Asp384, Arg400, and Gln477, supported by hydrophobic contacts with Phe484 and Trp480. Molecular dynamics simulations (200 ns) demonstrated stable binding, with root-mean-square deviation (RMSD) and fluctuation (RMSF) analyses confirming complex stability. Free energy decomposition underscored contributions from Asp384, Arg400, and Gln477, aligning with Vismodegib's binding mechanism. ZINC7263 adhered to drug-likeness criteria (Lipinski's rule of five, Jorgensen's rule of three) and exhibited favorable pharmacokinetics, including high oral absorption (89.45%) and blood-brain barrier permeability (logBB = -1.01). Induced-fit docking further validated its binding mode, highlighting a conserved interaction profile. These findings position ZINC7263 as a novel, potent SMO inhibitor with a stable binding affinity, dynamic interaction stability, and promising preclinical potential for targeting Hh-driven cancers. Its unique scaffold and optimized pharmacokinetic profile advocate for advanced in vitro and in vivo studies to translate these computational insights into therapeutic applications.