Venetoclax analogs as promising anticancer therapeutics via targeting Bcl-2 protein: in-silico drug discovery study

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• B-cell lymphoma 2 (Bcl-2) protein promotes cancer cell survival by inhibiting apoptosis.
• Targeting Bcl-2 is a key strategy in cancer therapy, with venetoclax as a notable inhibitor.
• There is a need for novel Bcl-2 inhibitors with improved efficacy and pharmacokinetic properties.

Purpose of the Study:

• To identify novel venetoclax analogs with enhanced binding affinity to Bcl-2 protein using in-silico methods.
• To evaluate the binding stability and pharmacokinetic profiles of the identified analogs.
• To provide potential anticancer leads for further in-vitro and in-vivo validation.

Main Methods:

• Virtual screening of a 4112-compound library against Bcl-2 protein using AutoDock Vina.
• Molecular dynamics (MD) simulations of promising analogs complexed with Bcl-2.
• Binding free energy calculations using the MM-GBSA approach.
• Pharmacokinetic property prediction.

Main Results:

• Two compounds, PubChem-873-158-83 and PubChem-148-422-478, exhibited superior binding affinities to Bcl-2 compared to venetoclax.
• MD simulations confirmed stable complex formation and interactions over 100 ns.
• Predicted pharmacokinetic profiles indicated favorable oral bioavailability for the identified analogs.
• Binding free energies were calculated as -69.1 kcal/mol and -62.4 kcal/mol, respectively.

Conclusions:

• The identified analogs represent promising novel candidates for Bcl-2 targeted cancer therapy.
• These compounds demonstrate enhanced binding and favorable pharmacokinetic properties.
• Further in-vitro and in-vivo studies are warranted to explore their full therapeutic potential.