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Record W4234736174 · doi:10.7287/peerj.preprints.521v1

Are improper kinetic models hampering drug development?

2014· preprint· en· W4234736174 on OpenAlexaff
Ryan Walsh

Bibliographic record

Venuenot available
Typepreprint
Languageen
FieldComputer Science
TopicComputational Drug Discovery Methods
Canadian institutionsCarleton University
Fundersnot available
KeywordsInhibitory postsynaptic potentialMechanism (biology)Drug developmentDrugOrder (exchange)ChemistrySimple (philosophy)Computer scienceComputational biologyPharmacologyBiologyNeuroscienceEconomicsEpistemologyPhilosophy

Abstract

fetched live from OpenAlex

Reproducibility of biological data is a significant problem in research today. One potential contributor to this, which has received little attention, is the over complication of enzyme kinetic inhibition models. This over complication of inhibitory models stems from the common use of the inhibitory term (1+[I]/K i ), an equilibrium binding term that does not distinguish between inhibitor binding and inhibitory effect. Since its initial appearance in the literature, around a century ago, the perceived mechanistic methods used in its production have spurred countless inhibitory equations. These equations are overly complex and are seldom compared to each other, which has destroyed their usefulness resulting in the proliferation and regulatory acceptance of simpler models such as ic50s for drug characterization. However, empirical analysis of inhibitory data recognizing the clear distinctions between inhibitor binding and inhibitory effect can produce simple logical inhibition models. In contrast to the common divergent practice of generating new inhibitory models for every inhibitory situation that presents itself, the empirical approach to inhibition modeling presented here, is broadly applicable allowing easy comparison and rational analysis of drug interactions. To demonstrate this, a simple kinetic model of DAPT, a compound which both activates and inhibits γ-secretase is examined using excel. The empirical kinetic method described here allows for a more in depth understanding of drug interactions and disease mechanism.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame machine prediction

Teacher imitation

Not 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.

metaresearch head score (Codex)0.037
metaresearch head score (Gemma)0.140
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesMetaresearch
Consensus categoriesnone
DomainCandidate signal: Methods · Consensus signal: none
Study designCandidate signal: Theoretical or conceptual · Consensus signal: Theoretical or conceptual
GenreCandidate signal: Commentary · Consensus signal: none
Teacher disagreement score0.963
Threshold uncertainty score0.198

Distilled classifier scores by category (both heads)

CategoryCodexGemma
Metaresearch0.0370.140
Meta-epidemiology (narrow)0.0010.002
Meta-epidemiology (broad)0.0030.002
Bibliometrics0.0010.002
Science and technology studies0.0010.004
Scholarly communication0.0060.009
Open science0.0050.002
Research integrity0.0030.006
Insufficient payload (model declined to judge)0.0030.002

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.

Opus teacher head0.050
GPT teacher head0.289
Teacher spread0.239 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.

Study designTheoretical or conceptual
DomainMethods
GenreCommentary

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".

Quick stats

Citations4
Published2014
Admission routes1
Has abstractyes

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