Three Decades of Targeting Falcipains to Develop AntiplasmodialAgents: What have we Learned and What can be Done Next?
Bibliographic record
Abstract
being responsible for the most lethal form of the disease. During the intraerythrocytic stage in the human hosts, malaria parasites multiply and degrade hemoglobin (Hb) using a battery of proteases, which include two cysteine proteases, falcipains 2 and 3 (FP-2 and FP-3). Due to their role as major hemoglobinases, FP-2 and FP-3 have been targeted in studies aiming to discover new antimalarials and numerous inhibitors with activity against these enzymes, and parasites in culture have been identified. Nonetheless, cross-inhibition of human cysteine cathepsins remains a serious hurdle to overcome for these compounds to be used clinically. In this article, we have reviewed key functional and structural properties of FP-2/3 and described different compound series reported as inhibitors of these proteases during decades of active research in the field. Special attention is also paid to the wide range of computer-aided drug design (CADD) techniques successfully applied to discover new active compounds. Finally, we provide guidelines that, in our understanding, will help advance the rational discovery of new FP-2/3 inhibitors.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".