Mohammadreza Ghaffarzadeh-Esfahani

Ali Motahharynia, Mohammadreza Ghaffarzadeh-Esfahani, Mahsa Sheikholeslami et al.

Current computational approaches for drug design typically focus on generating molecules conditioned on specific targets or general molecular properties, often neglecting the influence of disease context on target behavior and therapeutic outcomes. To address this gap, we introduce DrugGen-2, a novel generative model that designs small molecules conditioned on both disease ontology and target protein sequences. DrugGen-2 was developed by fine-tuning a pre-trained GPT-2 model on a curated dataset of approved drugs linked to their diseases and targets, using a two-step strategy of supervised fine-tuning followed by reinforcement learning via group relative policy optimization (GRPO). This process was guided by reward functions optimizing for chemical validity, novelty, diversity, and high predicted binding affinity. When evaluated on five protein targets relevant to diabetic nephropathy, DrugGen-2 significantly outperformed baseline models (DrugGPT and DrugGen). It demonstrated a superior capacity to generate unique molecules, exhibited greater structural similarity to approved drugs, and achieved improved predicted binding affinities across all targets. Molecular docking analyses further supported these findings, identifying candidate ligands with strong binding potential, including compounds with predicted affinities (-9.917, -9.485, and -9.367) exceeding those of reference drugs such as enalapril for angiotensin-converting enzyme (-8.283). By integrating disease-specific context into molecular generation, DrugGen-2 advances AI-assisted drug discovery, offering a powerful tool for de novo design and drug repurposing that accounts for the complex interplay between diseases and molecular targets.

Mohammadreza Ghaffarzadeh-Esfahani, Mahdi Ghaffarzadeh-Esfahani, Arian Salahi-Niri et al.

This study compared the performance of classical feature-based machine learning models (CMLs) and large language models (LLMs) in predicting COVID-19 mortality using high-dimensional tabular data from 9,134 patients across four hospitals. Seven CML models, including XGBoost and random forest (RF), were evaluated alongside eight LLMs, such as GPT-4 and Mistral-7b, which performed zero-shot classification on text-converted structured data. Additionally, Mistral- 7b was fine-tuned using the QLoRA approach. XGBoost and RF demonstrated superior performance among CMLs, achieving F1 scores of 0.87 and 0.83 for internal and external validation, respectively. GPT-4 led the LLM category with an F1 score of 0.43, while fine-tuning Mistral-7b significantly improved its recall from 1% to 79%, yielding a stable F1 score of 0.74 during external validation. Although LLMs showed moderate performance in zero-shot classification, fine-tuning substantially enhanced their effectiveness, potentially bridging the gap with CML models. However, CMLs still outperformed LLMs in handling high-dimensional tabular data tasks. This study highlights the potential of both CMLs and fine-tuned LLMs in medical predictive modeling, while emphasizing the current superiority of CMLs for structured data analysis.

Mohammadreza Ghaffarzadeh-Esfahani, Nahid Yousefian, Ebrahim Heidari-Farsani et al.

Extracting clinical information from medical transcripts in low-resource languages remains a significant challenge in healthcare natural language processing (NLP). This study evaluates a two-step pipeline combining Aya-expanse-8B as a Persian-to-English translation model with five open-source small language models (SLMs) -- Qwen2.5-7B-Instruct, Llama-3.1-8B-Instruct, Llama-3.2-3B-Instruct, Qwen2.5-1.5B-Instruct, and Gemma-3-1B-it -- for binary extraction of 13 clinical features from 1,221 anonymized Persian transcripts collected at a cancer palliative care call center. Using a few-shot prompting strategy without fine-tuning, models were assessed on macro-averaged F1-score, Matthews Correlation Coefficient (MCC), sensitivity, and specificity to account for class imbalance. Qwen2.5-7B-Instruct achieved the highest overall performance (median macro-F1: 0.899; MCC: 0.797), while Gemma-3-1B-it showed the weakest results. Larger models (7B--8B parameters) consistently outperformed smaller counterparts in sensitivity and MCC. A bilingual analysis of Aya-expanse-8B revealed that translating Persian transcripts to English improved sensitivity, reduced missing outputs, and boosted metrics robust to class imbalance, though at the cost of slightly lower specificity and precision. Feature-level results showed reliable extraction of physiological symptoms across most models, whereas psychological complaints, administrative requests, and complex somatic features remained challenging. These findings establish a practical, privacy-preserving blueprint for deploying open-source SLMs in multilingual clinical NLP settings with limited infrastructure and annotation resources, and highlight the importance of jointly optimizing model scale and input language strategy for sensitive healthcare applications.

Mohammadreza Ghaffarzadeh-Esfahani, Ali Motahharynia, Nahid Yousefian et al.

Drug discovery is a complex and resource-intensive process, making early prediction of approval outcomes critical for optimizing research investments. While classical machine learning and deep learning methods have shown promise in drug approval prediction, their limited interpretability constraints their impact. Here, we present DrugReasoner, a reasoning-based large language model (LLM) built on the LLaMA architecture and fine-tuned with group relative policy optimization (GRPO) to predict the likelihood of small-molecule approval. DrugReasoner integrates molecular descriptors with comparative reasoning against structurally similar approved and unapproved compounds, generating predictions alongside step-by-step rationales and confidence scores. DrugReasoner achieved robust performance with an AUC of 0.732 and an F1 score of 0.729 on the validation set and 0.725 and 0.718 on the test set, respectively. These results outperformed conventional baselines, including logistic regression, support vector machine, and k-nearest neighbors and had competitive performance relative to XGBoost. On an external independent dataset, DrugReasoner outperformed both baseline and the recently developed ChemAP model, achieving an AUC of 0.728 and an F1-score of 0.774, while maintaining high precision and balanced sensitivity, demonstrating robustness in real-world scenarios. These findings demonstrate that DrugReasoner not only delivers competitive predictive accuracy but also enhances transparency through its reasoning outputs, thereby addressing a key bottleneck in AI-assisted drug discovery. This study highlights the potential of reasoning-augmented LLMs as interpretable and effective tools for pharmaceutical decision-making.