L eishmaniasis is a prevalent disease that impacts 98 countries and territories, mainly in Africa, Asia, and South America. It can cause substantial illness and death, particularly in its visceral manifestation that can be specifically targeted in the development of medications to combat leishmaniasis. This study has found natural compounds with possible inhibitory activity against APX using a reliable and accurate QSAR model. Despite the severe side effects of current treatments and the absence of an effective vaccination, these compounds show promise as a potential treatment for the disease. Nine hit compounds were found, and subsequent molecular docking was performed. Estradiol cypionate showed the lowest binding energy (- 10.5 kcal/mol), thus showing the strongest binding, and also had the strongest binding affinity, with a ΔGTotal of - 26.31 ± 3.01 kcal/mol, second only to the control molecule. Additionally, three hits viz. cloxacillin-sodium (- 16.57 ± 2.89 kcal/mol), cinchonidine (- 16.04 ± 3.27 kcal/mol), and quinine hydrochloride dihydrate (13.38 ± 1.06 kcal/mol) also showed significant binding affinity. Multiple interactions between drugs and active site residues demonstrated a substantial binding affinity with the target protein. The identified compounds exhibited drug-like effects and were orally bioavailable based on their ADME-toxicology features. Overall, estradiol cypionate, cloxacillin sodium, cinchonidine, and quinine hydrochloride dihydrate all exhibited inhibitory effects on the APX enzyme of Leishmania donovani. These results suggest that further investigation is needed to explore the potential of developing novel anti-leishmaniasis drugs using these compounds.

College of Medicine Alfaisal University Riyadh Saudi Arabia 11 533

Department of Clinical Laboratory Sciences College of Applied Medical Sciences King Khalid University Abha Saudi Arabia 62 223

Department of Clinical Laboratory Sciences Faculty of Applied Medical Sciences Najran University Najran Saudi Arabia 61 441

Department of Medical Laboratories Technology College of Applied Medical Sciences Taibah University Madinah Saudi Arabia 41 411

Department of Microbiology National Reference Laboratory Cleveland Clinic Abu Dhabi Abu Dhabi United Arab Emirates 92 323

Department of Pathology College of Medicine Mohammed Bin Rashid University of Medicine and Health Sciences Dubai United Arab Emirates 505 055

Department of Public Health and Nutrition The University of Haripur Haripur Pakistan 22 610

Department of Public Health Faculty of Applied Medical Sciences Albaha University Albaha Saudi Arabia 65 77

Molecular Diagnostic Laboratory Johns Hopkins Aramco Healthcare 31 311 Dhahran Saudi Arabia

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