Artificial Intelligence Applied to the Rapid Identification of New Antimalarial Candidates with Dual‐Stage Activity
| Autor: | Arthur C. Silva, Kaira C. P. Tomaz, Joyce V. V. B. Borba, Gustavo Capatti Cassiano, Marilia N. N. Lima, Melina Mottin, Juliana Calit, Daniel Y. Bargieri, Sabrina Silva Mendonca, Fabio T. M. Costa, Carolina Horta Andrade |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
In silico
Plasmodium falciparum Drug Evaluation Preclinical Protozoan Proteins Computational biology 01 natural sciences Biochemistry Antimalarials Structure-Activity Relationship Parasitic Sensitivity Tests Artificial Intelligence parasitic diseases Drug Discovery Plasmodium berghei General Pharmacology Toxicology and Pharmaceutics Protein kinase A Protein Kinase Inhibitors Mitogen-Activated Protein Kinase Kinases Pharmacology Virtual screening Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Kinase Organic Chemistry biology.organism_classification 0104 chemical sciences 010404 medicinal & biomolecular chemistry CITOTOXICIDADE IMUNOLÓGICA Docking (molecular) Molecular Medicine Signal transduction |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.202000685 |
| Popis: | Increasing reports of multidrug-resistant malaria parasites urge the discovery of new effective drugs with different chemical scaffolds. Protein kinases play a key role in many cellular processes such as signal transduction and cell division, making them interesting targets in many diseases. Protein kinase 7 (PK7) is an orphan kinase from the Plasmodium genus, essential for the sporogonic cycle of these parasites. Here, we applied a robust and integrative artificial intelligence-assisted virtual-screening (VS) approach using shape-based and machine learning models to identify new potential PK7 inhibitors with in vitro antiplasmodial activity. Eight virtual hits were experimentally evaluated, and compound LabMol-167 inhibited ookinete conversion of Plasmodium berghei and blood stages of Plasmodium falciparum at nanomolar concentrations with low cytotoxicity in mammalian cells. As PK7 does not have an essential role in the Plasmodium blood stage and our virtual screening strategy aimed for both PK7 and blood-stage inhibition, we conducted an in silico target fishing approach and propose that this compound might also inhibit P. falciparum PK5, acting as a possible dual-target inhibitor. Finally, docking studies of LabMol-167 with P. falciparum PK7 and PK5 proteins highlighted key interactions for further hit-to lead optimization. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text