Integrating phenotype-based and target-based AI-driven drug discovery approaches to discover potent anti-leishmaniasis candidate drugs

• Grant number: 25/11727-6
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2026
• End date: December 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Ariel Mariano Silber
• Principal researcher abroad: Huanxiang Liu
• Institution abroad: Macau Polytechnic University , China
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Beatriz Simonsen Stolf ; Henry H Y Tong

Abstract

Leishmaniasis, a neglected tropical infectious disease, poses a severe threat to public health across 99 endemic countries and regions, yet safe and effective treatments remain critically lacking. There is an urgent need to develop novel therapeutics that are safe, potent, orally bioavailable, cost-effective, and capable of overcoming drug-resistant Leishmania parasites. To address this challenge, this project proposes an integrated AI-driven drug discovery strategy combining phenotypic screening and target-based drug design methods to discover anti-leishmanial candidate drugs. Our strategy encompasses four key components: 1) High-throughput phenotypic screening of compound libraries to identify active anti-leishmanial agents and generate robust training datasets for AI modeling. 2) Development of machine learning-based activity prediction models coupled with multi-scale virtual screening (HTVS¿SP¿XP) to prioritize candidate compounds. 3) Experimental validation: In vitro and in vivo evaluation of candidate compounds to confirm efficacy and prioritize lead optimization. 4) Rational drug design: Lead optimization via similarity-based searches, combinatorial library design, and multi-objective molecular generation model to refine potency, pharmacokinetics, and synthetic feasibility. The outcomes will deliver innovative drug discovery paradigms and promising anti-leishmanial candidates. This integrated approach not only addresses critical gaps in anti- leishmanial drug development but also establishes a transformative framework for drug discovery against neglected tropical diseases. (AU)