A benchmarking-informed structure-based virtual screening strategy targeting Lm-PTR1: Leveraging the Northern African...

Area of Science:

• Drug discovery and development
• Computational chemistry
• Parasitology

Background:

• Leishmaniasis is a neglected tropical disease with limited treatment options.
• New drug discovery strategies are crucial for combating leishmaniasis.
• Targeting the Leishmania major folate pathway, specifically pteridine reductase 1 (Lm-PTR1), is a promising approach.

Purpose of the Study:

• To develop and validate a structure-based virtual screening (SBVS) strategy for leishmaniasis drug discovery.
• To identify novel inhibitors of Leishmania major pteridine reductase 1 (Lm-PTR1).
• To assess the binding stability and potential efficacy of identified compounds.

Main Methods:

• Compiled bioactive molecules against Lm-PTR1.
• Generated a DEKOIS 2.0 benchmark set to evaluate docking tools (FRED, AutoDock Vina, PLANTS).
• Performed ensemble virtual screening using FRED against the NANPDB database.
• Conducted molecular dynamics (MD) simulations and MM-GBSA calculations to assess binding stability.

Main Results:

• FRED demonstrated superior screening performance (pROC-AUC 0.84, EF 1% 12.5).
• Three candidate compounds were nominated: Anastatin A, valoneic acid dilactone, and 1,6-di-O-galloyl glucose.
• MD simulations and MM-GBSA confirmed stable binding for valoneic acid dilactone and 1,6-di-O-galloyl glucose, outperforming folic acid.

Conclusions:

• Valoneic acid dilactone and 1,6-di-O-galloyl glucose show potential to inhibit Lm-PTR1 by blocking folic acid binding.
• These compounds are recommended for in vitro evaluation in leishmaniasis drug discovery.
• The validated benchmarking strategy can be applied to other SBVS campaigns.