Design and screening of novel molecular compounds targeting lactate dehydrogenase of Babesia microti
Bibliographic record
Abstract
Abstract Background Human babesiosis is caused by several species within the Babesia genus, primarily Babesia microti , Babesia duncani , and Babesia divergens , all of which infect human red blood cells (RBCs). Clinically, the disease manifests with symptoms such as fever, anemia, jaundice, and hemoglobinuria, with B. microti being the most prevalent of these species. Our previous research has shown that B. microti primarily relies on lactate dehydrogenase (LDH)-mediated anaerobic glycolysis, rather than the tricarboxylic acid cycle (TCA cycle), to generate ATP for its intracellular survival. Because LDH is a promising drug target, it can be inhibited by compounds such as gossypol and 3,5-dihydroxy-2-naphthoxylic acid (DHNA). In this study, we conduct a structure-based optimization of DHNA, leading to the development of a novel library of compounds derived from its structure. Methods Two compounds were identified and synthesized through molecular docking, on the basis of the crystal structure of Babesia microti lactate dehydrogenase (BmLDH). The effects of these compounds were evaluated using several methods, including surface plasmon resonance (SPR) assays, enzyme activity inhibition tests, in vitro growth inhibition assays against B. microti , and mammalian cytotoxicity tests. Results Compounds target A (TA) (−36.0) and B (TB) (−43.8), both exhibiting low CDOCKER energy values, achieved final purities of 96.6% and 97.5%, respectively. Surface plasmon resonance (SPR) experiments showed that TA and TB had comparable dissociation constant ( K D ) values of 11.3 × 10 −6 M and 13.2 × 10 −6 M, respectively. However, enzyme activity inhibition assays indicated that TB was more potent, with an half-maximal inhibitory concentration (IC 50 ) value of 23.8 μM, compared with TA’s IC 50 of 71.6 μM. Additionally, TB demonstrated a strong ability to inhibit the in vitro growth of B. microti , with an IC 50 value of 111.7 μM. Conclusions In this study, two compounds capable of inhibiting the growth of B. microti were obtained. Although both compounds showed moderate inhibitory activity against recombinant BmLDH (rBmLDH) and the growth of B. microti , there is potential to enhance their efficacy through further structural modifications, particularly of compound TB. Graphical Abstract
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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".