Repurposing of DrugBank molecules as dual non-hydroxamate HDAC8 and HDAC2 inhibitors by pharmacophore modeling,...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Histone deacetylase 8 (HDAC8) and HDAC2 are overexpressed in cervical cancer, presenting a therapeutic target.
• Existing selective HDAC inhibitors often are hydroxamic acids with adverse side effects due to zinc chelation.
• Dual-targeted HDAC inhibitors for cervical cancer are underexplored, especially non-hydroxamate compounds.

Purpose of the Study:

• To identify novel, non-hydroxamate dual inhibitors of HDAC8 and HDAC2 using repurposed DrugBank molecules.
• To evaluate the potential of these compounds for cervical cancer management.
• To assess the safety and efficacy profiles of identified inhibitors through in silico methods.

Main Methods:

• Utilized a two-tier virtual screening approach including e-pharmacophore modeling and protein-based virtual screening (PBVS).
• Employed Glide XP docking into HDAC8 and HDAC2 crystal structures, followed by re-docking into other HDAC isoforms for selectivity.
• Conducted molecular dynamics simulations, MM-GBSA binding energy calculations, in silico ADMET, and cytotoxicity predictions.

Main Results:

• Identified 658 hits from 12,223 DrugBank molecules with initial screening, narrowing down to 52 top hits after Glide XP docking.
• DB11747, DB03973, DB03812, DB07890, and DB03448 emerged as lead compounds with stable interactions and binding energies for both HDAC8 and HDAC2.
• In silico studies indicated favorable pharmacokinetic and safety profiles, alongside potent anticancer activity for the identified compounds.

Conclusions:

• Repurposing DrugBank molecules yielded promising non-hydroxamate dual inhibitors of HDAC8 and HDAC2 for cervical cancer.
• The identified lead compounds demonstrate potential for effective and safer cervical cancer therapy.
• Further experimental validation is warranted to confirm the therapeutic efficacy of these novel inhibitors.