A Virtual Screening Approach to Evaluate the Multitarget Potential of a Chalcone Library with Binding Properties to Oligopeptidase B and Cysteine Proteinase B from Leishmania (Viannia) braziliensis

Leishmaniasis remains a significant public health problem in Brazil, particularly due to <i>Leishmania (Viannia) braziliensis</i>, which is associated with severe dermatological syndromes. The current treatments are limited by toxicity and uncertain efficacy, highlighting the need for new compounds with pharmacological potential. This study investigates chalcones as multitarget binding agents for oligopeptidase B (OPB) and cysteine proteinase B (CPB), which are critical pathogenic determinants of <i>L. (V.) braziliensis</i>. The methodology involved replacing methoxy groups with aryl motifs at various positions within the chalcone structures and introducing specific functional groups at the C-4 position. This was followed by a virtual screening approach using molecular docking to assess interactions with the target proteinases. Several chalcones from the virtual library (<i>n</i> = 178) exhibited high binding affinities for OPB and CPB, outperforming control ligands. A total of 30 chalcones with multitarget potential were identified, with fluorinated compounds C-191 and C-135 emerging as promising inhibitors, distinguished by the best energy rankings for both enzymes. ADMET analyses confirmed the viability of these chalcones as drug candidates, with most adhering to Lipinski's rules. These data suggest that chalcones may provide new multitarget treatment options for leishmaniasis.