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Bibliographic Details
Main Author:	Pirolo, Andrés Sebastián
Format:	Recurso digital
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Published:	Zenodo 2026
Subjects:	New Chemical Entity Chagas disease
Online Access:	https://doi.org/10.5281/zenodo.19489216
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Chagas disease, caused by Trypanosoma cruzi, affects an estimated 6–7 million people worldwide, with no approved therapy for the chronic phase. The cysteine protease cruzipain is the parasite’s principal virulence factor and a validated drug target; yet no small-molecule inhibitor has reached clinical approval. This work reports the application of a custom rigid-body geometric docking engine to the cruzipain active site (PDB 1AIM) to identify novel non-covalent inhibitor scaffolds. Four macrocyclic candidates (NCE1–NCE4) were evaluated against the S1/S2 binding pocket using a two-layer scoring function combining contact-count complementarity and hydrogen-bond geometry at the catalytic triad (Cys25/His159/Gly66). All four candidates achieved docking scores between 64 and 70, below the co-crystallised reference inhibitor ZYA280 (score 97), confirming correct pocket targeting. Comprehensive ADME profiling via SwissADME demonstrated that two candidates (NCE2 and NCE4) satisfy all Leadlikeness criteria with zero PAINS and zero Brenk alerts, consensus LogP below 1.0, TPSA below 100 Å², and high predicted gastrointestinal absorption. Exhaustive searches across PubChem, ChEMBL, ZINC, SureChEMBL, and patent databases confirm all four structures as absolute New Chemical Entities with no prior pharmacological record. The complete pipeline — structural pocket extraction, geometric docking, and ADME evaluation — runs on standard consumer hardware without GPU acceleration, demonstrating the feasibility of resource-independent drug discovery for neglected tropical diseases.

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