Covalent Inhibitor Screening for Targeting LOXL2: Studied by Virtual Screening and Experimental Validation

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme implicated in promoting tumor metastasis and invasion.
• Disulfide bonds are critical for LOXL2 bioactivity and can be targeted by small molecules.
• Covalent inhibitors offer a strategy to modulate LOXL2 function by blocking disulfide bond formation.

Purpose of the Study:

• To screen for and identify novel covalent inhibitors of LOXL2.
• To investigate the potential of targeting LOXL2 disulfide bonds for cancer therapy.

Main Methods:

• Virtual screening of covalent molecule libraries using Schrödinger's CovDock.
• Structure optimization and conformation generation using LigPrep.
• Experimental validation through wound-healing assays.

Main Results:

• Eight potential covalent inhibitors were identified from 7,908 candidates.
• All selected compounds passed ADMET evaluation.
• Compound F50972176 demonstrated significant inhibition of cancer cell migration.

Conclusions:

• Virtual screening combined with experimental validation is effective for identifying LOXL2 covalent inhibitors.
• The compound F50972176 shows potential for inhibiting esophageal squamous cell carcinoma cell migration.