arXiv subjects

Dariusz Plewczynski

Publications and source records attributed to Dariusz Plewczynski.

8 recordsLinked to original sources

arXiv2026

The Geometry of Activity Cliffs: Representation Dependence and Multi-Scale Characterization of Activity Landscapes

Activity cliffs, structurally similar compounds with large potency differences, are widely treated as intrinsic features of chemical datasets. We argue that apart from target biology, much of our cliff understanding is a consequence of the geometry induced by the chosen molecular representation, not a property of a molecule pair itself. We designed a six-step pipeline to systematically test this hypothesis. The pipeline consists of: assessing pairwise distance geometry, cliff enrichment, activity gradient distribution, persistent homology of the cliff subspace, predictive benchmarking for a chosen pair of an embedding and a metric, and eventually, analysis of the matched molecular pairs and stereoisomers. We applied the pipeline to fifteen configurations of embeddings and metrics to build a benchmark across three distinctive datasets known of activity cliffs challenges. No representation excels on all criteria: Morgan Tanimoto provides the strongest cliff enrichment and cross-scaffold generalization; MolFormer cosine provides the only meaningful stereochemical sensitivity; MACCS and RDKit Dice fingerprints are most sensitive to matched-molecular-pair transformations; ChemBERTa fails uniformly due to embedding collapse. These findings are not a ranking. They reflect the fact that different representations encode different aspects of molecular recognition, and that choosing one implicitly defines what an activity cliff actually is.

q-bio.QM↗

arXiv2026

An explainable hypothesis-driven approach to Drug-Induced Liver Injury with HADES

Drug-induced liver injury (DILI) remains a leading cause of late-stage clinical trial attrition. However, existing computational predictors primarily rely on binary classification, a framing that limits generalization and yields no mechanistic insight to guide translational decisions. We argue that DILI prediction is better posed as an explainable hypothesis-generation problem. To support this shift, we introduce the DILER Benchmark, a dataset that extends beyond binary labels by augmenting a curated set of molecules with mechanistic hepatotoxicity hypotheses derived from biomedical literature. We further present HADES, an agentic system designed to generate transparent and auditable reasoning traces. By combining molecular-level predictions, metabolite decomposition, structural understanding, and toxicity pathway evidence, HADES mechanistically assesses DILI risk. Evaluated on the DILER Benchmark, HADES outperforms existing models in binary classification, achieving a ROC-AUC of 0.68 on the Test Set and 0.59 on the challenging Post-2021 Set, compared with 0.63 and 0.50 for DILI-Predictor, respectively. More importantly, we establish a baseline for mechanistic hypothesis generation, where HADES achieves a Hypothesis Alignment Fuzzy Jaccard Index of 0.16. This result underscores the inherent complexity of the task while highlighting the need for advanced explainable approaches in predictive toxicology.

cs.AI↗

arXiv2024

RapidDock: Unlocking Proteome-scale Molecular Docking

Accelerating molecular docking -- the process of predicting how molecules bind to protein targets -- could boost small-molecule drug discovery and revolutionize medicine. Unfortunately, current molecular docking tools are too slow to screen potential drugs against all relevant proteins, which often results in missed drug candidates or unexpected side effects occurring in clinical trials. To address this gap, we introduce RapidDock, an efficient transformer-based model for blind molecular docking. RapidDock achieves at least a $100 \times$ speed advantage over existing methods without compromising accuracy. On the Posebusters and DockGen benchmarks, our method achieves $52.1\%$ and $44.0\%$ success rates ($\text{RMSD}<2$Å), respectively. The average inference time is $0.04$ seconds on a single GPU, highlighting RapidDock's potential for large-scale docking studies. We examine the key features of RapidDock that enable leveraging the transformer architecture for molecular docking, including the use of relative distance embeddings of $3$D structures in attention matrices, pre-training on protein folding, and a custom loss function invariant to molecular symmetries.

q-bio.BM↗

arXiv2014

Role of the host genetic variability in the influenza-A virus susceptibility; a review

The aftermath of influenza infection is determined by a complex set of host-pathogen interactions, where genomic variability on both viral and host sides influences the final outcome. Although there exists large body of literature describing influenza virus variability, only a very small fraction covers the issue of host variance. The goal of this review is to explore the variability of host genes responsible for host-pathogen interactions, paying particular attention to genes responsible for the presence of sialylated glycans in the host endothelial membrane, mucus, genes used by viral immune escape mechanisms, and genes particularly expressed after vaccination, since they are more likely to have a direct influence on the infection outcome.

q-bio.PE↗

arXiv2013

Information-sharing and aggregation models for interacting minds

We study mathematical models of the collaborative solving of a two-choice discrimination task. We estimate the difference between the shared performance for a group of n observers over a single person performance. Our paper is a theoretical extension of the recent work of Bahrami et al. (2010) from a dyad (a pair) to a group of n interacting minds. We analyze several models of communication, decision-making and hierarchical information-aggregation. The maximal slope of psychometric function (closely related to the percentage of right answers vs. easiness of the task) is a convenient parameter characterizing performance. For every model we investigated, the group performance turns out to be a product of two numbers: a scaling factor depending of the group size and an average performance. The scaling factor is a power function of the group size (with the exponent ranging from 0 to 1), whereas the average is arithmetic mean, quadratic mean, or maximum of the individual slopes. Moreover, voting can be almost as efficient as more elaborate communication models, given the participants have similar individual performances.

physics.soc-ph↗

arXiv2010

Landau Theory of Adaptive Integration in Computational Intelligence

Computational Intelligence (CI) is a sub-branch of Artificial Intelligence paradigm focusing on the study of adaptive mechanisms to enable or facilitate intelligent behavior in complex and changing environments. There are several paradigms of CI [like artificial neural networks, evolutionary computations, swarm intelligence, artificial immune systems, fuzzy systems and many others], each of these has its origins in biological systems [biological neural systems, natural Darwinian evolution, social behavior, immune system, interactions of organisms with their environment]. Most of those paradigms evolved into separate machine learning (ML) techniques, where probabilistic methods are used complementary with CI techniques in order to effectively combine elements of learning, adaptation, evolution and Fuzzy logic to create heuristic algorithms that are, in some sense, intelligent. The current trend is to develop consensus techniques, since no single machine learning algorithms is superior to others in all possible situations. In order to overcome this problem several meta-approaches were proposed in ML focusing on the integration of results from different methods into single prediction. We discuss here the Landau theory for the nonlinear equation that can describe the adaptive integration of information acquired from an ensemble of independent learning agents. The influence of each individual agent on other learners is described similarly to the social impact theory. The final decision outcome for the consensus system is calculated using majority rule in the stationary limit, yet the minority solutions can survive inside the majority population as the complex intermittent clusters of opposite opinion.

stat.ML↗

arXiv2009

Mean-Field Theory of Meta-Learning

We discuss here the mean-field theory for a cellular automata model of meta-learning. The meta-learning is the process of combining outcomes of individual learning procedures in order to determine the final decision with higher accuracy than any single learning method. Our method is constructed from an ensemble of interacting, learning agents, that acquire and process incoming information using various types, or different versions of machine learning algorithms. The abstract learning space, where all agents are located, is constructed here using a fully connected model that couples all agents with random strength values. The cellular automata network simulates the higher level integration of information acquired from the independent learning trials. The final classification of incoming input data is therefore defined as the stationary state of the meta-learning system using simple majority rule, yet the minority clusters that share opposite classification outcome can be observed in the system. Therefore, the probability of selecting proper class for a given input data, can be estimated even without the prior knowledge of its affiliation. The fuzzy logic can be easily introduced into the system, even if learning agents are build from simple binary classification machine learning algorithms by calculating the percentage of agreeing agents.

stat.ML↗

arXiv2009

BRAINSTORMING: Consensus Learning in Practice

We present here an introduction to Brainstorming approach, that was recently proposed as a consensus meta-learning technique, and used in several practical applications in bioinformatics and chemoinformatics. The consensus learning denotes heterogeneous theoretical classification method, where one trains an ensemble of machine learning algorithms using different types of input training data representations. In the second step all solutions are gathered and the consensus is build between them. Therefore no early solution, given even by a generally low performing algorithm, is not discarder until the late phase of prediction, when the final conclusion is drawn by comparing different machine learning models. This final phase, i.e. consensus learning, is trying to balance the generality of solution and the overall performance of trained model.

stat.ML↗