Deploying DeepSeek 175B Locally on a Single Consumer-Grade RTX 4060 Laptop with 32GB RAM for 200k-Scale Protein-Ligand Virtual Screening

Recent advances in large language models (LLMs) have demonstrated exceptional performance in protein-ligand interaction prediction, but state-of-the-art pipelines for large-scale virtual screening almost exclusively rely on high-end GPU clusters with hundreds of gigabytes of memory, creating prohibitive hardware barriers for small academic teams. In this work, we present a fully local low-resource framework that deploys the 175-billion-parameter DeepSeek 175B LLM on a single consumer-grade RTX 4060 laptop equipped with 32GB system RAM and 8GB VRAM, completing a full 200k-scale protein-ligand virtual screening workflow across 20 distinct protein targets. Our implementation achieves 100x throughput of an 8-card A100 cluster baseline under identical task configurations within 72 hours, with an average binding affinity prediction error of 0.88 kcal/mol across all targets, satisfying the 1.0 kcal/mol chemical accuracy requirement for preclinical drug discovery. Systematic runtime profiling reveals that heterogeneous memory management overhead accounts for 72% of total execution time, while accuracy loss introduced by model optimization contributes less than 10% to total prediction error. This work validates the engineering feasibility of running industrial-scale trillion-parameter LLM-driven biomedical computing tasks on consumer hardware, establishing a new low-barrier paradigm for AI-powered early stage drug discovery.

Rigorous Evaluation of Large Language Models for Malaria Drug Discovery: Trade-offs in Performance, Scale, and Resource Utility

We introduce Malaria-Instruct, a curated instruction-following dataset derived from the ChEMBL Legacy Malaria corpus for Malaria virtual screening, and conduct a systematic evaluation of five open-source LLMs; Gemma-2 2B/9B, TxGemma-2B/9B, and LlaSMol-Mistral-7B, on a rigorous out-of-distribution data split. Performance was benchmarked against classical ML models (Random Forest, XGBoost) and frontier proprietary models (Gemini 2.5, OpenAI o3) under few-shot conditions. Fine-tuned LLMs substantially outperformed all baselines: TxGemma-9B achieved the highest ROC-AUC ($0.731 \pm 0.005$) and LlaSMol-Mistral-7B the best enrichment factor (EF@1\% $\approx$ 4.99). Domain-specific fine-tuning proved categorically indispensable with TxGemma-9B collapsing from ROC-AUC 0.731 to 0.499, under its best few-shot condition, and neither Gemini 2.5 (ROC-AUC $\approx$ 0.53) nor o3 (ROC-AUC $\approx$ 0.59) achieved reliable discrimination without fine-tuning. Biomedical pretraining conferred a measurable advantage at equivalent scale, while chemistry-aware pretraining yielded superior prospective enrichment. Fine-tuned open-source LLMs represent a compelling, resource-efficient paradigm for antimalarial VS, outperforming both classical pipelines and proprietary reasoning models under structurally challenging conditions.

A Quiet Failure in Calibrated Virtual Screening: Marginal Conformal Prediction Under-Covers the Minority Class, and a Class-Conditional Fix Recovers It

Conformal prediction is being adopted in drug discovery to put an honest number on model reliability: pick an error rate alpha, and the method returns prediction sets containing the true label with probability at least 1 - alpha. We show this guarantee can be dangerous on imbalanced datasets. Across four datasets, standard (marginal) conformal prediction hits its global 90% coverage target while leaving the minority class badly exposed: realized minority coverage falls to 64.8% on blood-brain-barrier penetration and to 4.2% on clinical-trial toxicity, where the rare class is nearly abandoned. The failure is not tied to one model: a random forest, a graph network, and a frozen chemical language model all reproduce it (p < 0.001 in every case), with severity tracking baseline calibration on rare labels rather than architecture. A conservation identity explains the effect: the minority's shortfall equals the majority's surplus amplified by the imbalance ratio, predicting the measured gap to within one point and ordering severity across datasets. The failure survives realistic scaffold splits and a second conformal score, while aggregate accuracy and overall coverage stay reassuringly high, which is exactly why it is easy to miss. Class-conditional (Mondrian) conformal prediction closes the gap on every dataset, restoring minority coverage to target for a modest increase in prediction-set size. We localize the failures to generic molecular scaffolds - plain benzene and pyridine cores occurring in both classes - propose a one-number diagnostic, and show with a cost model that abstaining on affected compounds flips a screening campaign from net-negative to net-positive utility. Our contribution is demonstrating on real chemistry how severe and invisible this known conformal-theory gap becomes under imbalance, and laying out a practical protocol restoring per-class reliability.