Structure and Specificity of a Human Valacyclovir Activating Enzyme: A Homology Model of BPHL
Bibliographic record
Abstract
Biphenyl hydrolase-like (BPHL) protein is a novel serine hydrolase which has been identified as human valacyclovirase (VACVase), catalyzing the hydrolytic activation of valine ester prodrugs of the antiviral drugs acyclovir and ganciclovir as well as other amino acid ester prodrugs of therapeutic nucleoside analogues. The broad specificity for nucleoside analogues as parent drugs suggests that BPHL may be particularly useful as a molecular target for prodrug activation. In order to develop an initial structural view of the specificity of BPHL, a homology model of BPHL based on the crystal structure of 2-hydroxy-6-oxo-7-methylocta-2,4-dienoate hydrolase was developed using the Molecular Operating Environment package (Chemical Computing Group, Montreal, Quebec), evaluated for its stereochemical quality and identification of free cysteines, and used in a molecular docking study. The BPHL model has residues S122, H255, and D227 comprising the putative catalytic triad in proximity and potential charge-charge interaction sites, M52 or D123 for the alpha-amino group. The model also suggested that the structural preference of BPHL for hydrophobic amino acyl promoieties and its limited activity for the secondary alcohol substrates may be attributed to the hydrophobic acyl-binding site formed by residues I158, G161, I162, and L229, and the spatial constraint around the catalytic site by a loop on one side, the active serine and histidine on the other side, and L53 and L179 on top. In addition, the broad specificity for nucleoside analogues may be due to the relatively less constrained nucleoside-binding site opening toward the entrance of the substrate-binding pocket. The homology model of BPHL provides a basis for further investigation of the catalytic and active site residues, can account for the observed structure activity profile of BPHL, and will be useful in the design of nucleoside prodrugs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".