This Week In Cheminformatics: Issue #028
Fingerprint benchmarking for metabolomics, Harmonizing pharmacogenomics DBs, Fast TS guesser in VeloxChem and a long list of papers
Highlights
Count your bits: fingerprint benchmarking to assess broad chemical space representation
Here, Huber & Pollmann benchmark molecular fingerprints on virtual screening retrieval across specificity, compound-size dependence, ranking agreement, correlation with MCES scores, and chemical class prediction on large, heterogeneous natural product/metabolomics datasets. The key findings are count fingerprints are almost always better than binary for this task, folding-induced bit collisions are far worse than commonly assumed for high-occupancy fingerprints like RDKit and MAP4 (folded MAP4 showed essentially zero correlation with rascalMCES on their data, while unfolded MAP4 hit ~0.6), and larger Morgan/FCFP radii (r=9) consistently performed well across tasks. They also introduce a “frequency-folding” alternative that keeps a fixed vector size while avoiding collisions by selecting the most occupied bits from an unfolded representation. This works well for Morgan/FCFP but not for RDKit, which they attribute to information loss given RDKit’s very high bit occupancy. The code is here. Good read!
Harmonization and integration of pharmacogenomics screens
Chen et al. evaluate how different curve-fitting functions and drug concentration windows impact cross-database reproducibility of large pharmacogenomics screens like GDSC, CTRP, etc. Interestingly, the authors demonstrate that calculating the AUC derived from a sigmoidal fit over a strictly filtered / truncated data with shared dose range (0.03 µM to 10.00 µM) outperforms full-range AUC, IC50, and EC50 metrics in cross-platform agreement. This “TruncAUC” protocol maximizes pairwise reproducibility and improves the identification of sensitive cell lines. Code can be found here.
From SMILES Codes for Reactants and Products to Transition States With VeloxChem
van Hoorn et al. propose a method for automatically generating initial transition state (TS) guesses directly from reactant and product SMILES. They do this by constructing and interpolating between reactant and product force fields to approximate the potential energy surface along the reaction coordinate. The method produces reliable starting geometries for single-ended TS optimizations at a fraction of the usual cost. Benchmarks across 121 diverse reactions demonstrated convergence for 115 transition states, requiring an average of just 107 gradient evaluations per reaction. It is implemented natively in VeloxChem.
Long List
Cheminformatics
FragScan: A Quantitative Fragment Scanning Strategy for Rational Drug Discovery
GeoPep: A Geometry-Aware Masked Language Model for Protein-Peptide Binding Site Prediction
Cluster-based virtual reaction generation with reaction site-centered buffer zone
SPPIDER-seq: sequence-based partner-aware predictor of protein-protein interaction sites
A survey of models composed of graph neural networks and large language models for molecular science
MetagenomicKG: a knowledge graph for metagenomic applications
Computational tool choice impacts CRISPR spacer-protospacer detection
DeepKbhb: Context-Aware Prediction of Human Lysine β-Hydroxybutyrylation Sites
Simulation Guided Design of a Potentially Hyperactive Ice Nucleating Protein
MolPy: A Large Language Model-Friendly Toolkit for Reactive Topology Editing in Polymer Simulations
Setting the Bases of the Photogenotoxicity of p-Aminobenzoic Acid
Multimodal feature fusion for molecular property classification
P2MAT: A machine learning (ML) driven software for Property Prediction of MATerial
PES2MP: A Python Application for Automating Collisional Dynamics of Linear Rigid-Rotors
RANQSAR: a standalone open-source application for reproducible machine learning-based QSAR analysis
KCFtools: rapid alignment-free method for introgression screening and GWAS using k-mer profiles
QSAR in the Browser: An Interactive Cheminformatics Web Application
Knowledge Distillation of a Protein Language Model Yields a Foundational Implicit Solvent Model
MedChem
Navigating Misfolded Terrain: ER-Associated Degradation of Membrane Proteins
Recent Highlights in the Discovery and Design of Antibody–Drug Conjugates
Other
Late-Stage Carbonyl Removal via Sequential Double Carbon–Carbon Bond Cleavage
To Biotic or Abiotic: Biohybrid Systems for Artificial Photosynthesis
Palate Cleanser
Best,
Manas