However, these methods have notable limitations.

Following this thought, we recast virtual screening as an information retrieval task, i.e., given a

Protein-ligand binding prediction is a fundamental problem in AI-driven drug discovery.

Structure-based and ligand-based computational drug design have traditionally relied on disjoint data sources and modeling assumptions, limiting their joint use at scale. In this work, we introduce Contrastive Geometric Learning for Unified Computational Drug Design (ConGLUDe), a single contrastive geometric model that unifies structure- and ligand-based training. ConGLUDe couples a geometric protein encoder that produces whole-protein representations and implicit embeddings of predicted binding sites with a fast ligand encoder, removing the need for pre-defined pockets. By aligning ligands with both global protein representations and multiple candidate binding sites through contrastive learning, ConGLUDe supports ligand-conditioned pocket prediction in addition to virtual screening and target fishing, while being trained jointly on protein-ligand complexes and large-scale bioactivity data. Across diverse benchmarks, ConGLUDe achieves state-of-the-art zero-shot virtual screening performance in settings where no binding pocket information is provided as input, substantially outperforms existing methods on a challenging target fishing task, and demonstrates competitive ligand-conditioned pocket selection. These results highlight the advantages of unified structure-ligand training and position ConGLUDe as a step toward general-purpose foundation models for drug discovery.

Structure-based drug design (SBDD) aims to discover drug candidates by finding molecules (ligands) that bind tightly to a disease-related protein (targets), which is the primary approach to computer-aided drug discovery. Recently, applying deep generative models for three-dimensional (3D) molecular design conditioned on protein pockets to solve SBDD has attracted much attention, but their formulation as probabilistic modeling often leads to unsatisfactory optimization performance. On the other hand, traditional combinatorial optimization methods such as genetic algorithms (GA) have demonstrated state-of-the-art performance in various molecular optimization tasks. However, they do not utilize protein target structure to inform design steps but rely on a random-walk-like exploration, which leads to unstable performance and no knowledge transfer between different tasks despite the similar binding physics. To achieve a more stable and efficient SBDD, we propose Reinforced Genetic Algorithm (RGA) that uses neural models to prioritize the profitable design steps and suppress random-walk behavior. The neural models take the 3D structure of the targets and ligands as inputs and are pre-trained using native complex structures to utilize the knowledge of the shared binding physics from different targets and then fine-tuned during optimization. We conduct thorough empirical studies on optimizing binding affinity to various disease targets and show that RGA outperforms the baselines in terms of docking scores and is more robust to random initializations. The ablation study also indicates that the training on different targets helps improve the performance by leveraging the shared underlying physics of the binding processes.

Force field-based molecular dynamics (MD) simulations are indispensable for probing the structure, dynamics, and functions of biomolecular systems, including proteins and protein-ligand complexes. Despite their broad utility in drug discovery and protein engineering, the technical complexity of MD setup, encompassing parameterization, input preparation, and software configuration, remains a major barrier for widespread and efficient usage. Agentic LLMs have demonstrated their capacity to autonomously execute multi-step scientific processes, and to date, they have not successfully been used to automate protein-ligand MD workflows. Here, we present DynaMate, a modular multi-agent framework that autonomously designs and executes complete MD workflows for both protein and protein-ligand systems, and offers free energy binding affinity calculations with the MM/PB(GB)SA method. The framework integrates dynamic tool use, web search, PaperQA, and a self-correcting behavior. DynaMate comprises three specialized modules, interacting to plan the experiment, perform the simulation, and analyze the results. We evaluated its performance across twelve benchmark systems of varying complexity, assessing success rate, efficiency, and adaptability. DynaMate reliably performed full MD simulations, corrected runtime errors through iterative reasoning, and produced meaningful analyses of protein-ligand interactions. This automated framework paves the way toward standardized, scalable, and time-efficient molecular modeling pipelines for future biomolecular and drug design applications.

The diverse nature of protein prediction tasks has traditionally necessitated specialized models, hindering the development of broadly applicable and computationally efficient Protein Language Models (PLMs). In this work, we introduce Prot2Token, a unified framework that overcomes these challenges by converting a wide spectrum of protein-related predictions-from sequence-level properties and residue-specific attributes to complex inter-protein interactions-into a standardized next-token prediction format. At its core, Prot2Token employs an autoregressive decoder, conditioned on embeddings from pre-trained protein encoders and guided by learnable task tokens, to perform diverse predictions. This architecture uniquely facilitates multi-task learning, enabling general-purpose decoders to generalize across five distinct categories. We present extensive experimental validation across a variety of benchmarks, demonstrating Prot2Token's predictive power in different types of protein-prediction tasks. In 3D structure prediction, Prot2Token delivers substantial speedups (up to 1000x faster than AlphaFold2 with MSA on the same hardware) while, across other numerous tasks, matching or surpassing specialized methods. Beyond that, we introduce an auxiliary self-supervised decoder pre-training approach to improve spatially sensitive task performance. Prot2Token thus offers a step towards standardizing biological prediction into a generative interface, promising to accelerate biological discovery and the development of novel therapeutics. The code is available at https://github.com/mahdip72/prot2token .

Structure-based drug design (SBDD) focuses on designing small-molecule ligands that bind to specific protein pockets. Computational methods are integral in modern SBDD workflows and often make use of virtual screening methods via docking or pharmacophore search. Modern generative modeling approaches have focused on improving novel ligand discovery by enabling de novo design. In this work, we recognize that these tasks share a common structure and can therefore be represented as different instantiations of a consistent generative modeling framework. We propose a unified approach in OMTRA, a multi-modal flow matching model that flexibly performs many tasks relevant to SBDD, including some with no analogue in conventional workflows. Additionally, we curate a dataset of 500M 3D molecular conformers, complementing protein-ligand data and expanding the chemical diversity available for training. OMTRA obtains state of the art performance on pocket-conditioned de novo design and docking; however, the effects of large-scale pretraining and multi-task training are modest. All code, trained models, and dataset for reproducing this work are available at https://github.com/gnina/OMTRA

Structure-Based drug design (SBDD) has emerged as a popular approach in drug discovery, leveraging three-dimensional protein structures to generate drug ligands. However, existing generative models encounter several key challenges: (1) incorporating boundary condition constraints, (2) integrating hierarchical structural conditions, and (3) ensuring spatial modeling fidelity. To address these limitations, we propose SculptDrug, a spatial condition-aware generative model based on Bayesian flow networks (BFNs). First, SculptDrug follows a BFN-based framework and employs a progressive denoising strategy to ensure spatial modeling fidelity, iteratively refining atom positions while enhancing local interactions for precise spatial alignment. Second, we introduce a Boundary Awareness Block that incorporates protein surface constraints into the generative process to ensure that generated ligands are geometrically compatible with the target protein. Third, we design a Hierarchical Encoder that captures global structural context while preserving fine-grained molecular interactions, ensuring overall consistency and accurate ligand-protein conformations. We evaluate SculptDrug on the CrossDocked dataset, and experimental results demonstrate that SculptDrug outperforms state-of-the-art baselines, highlighting the effectiveness of spatial condition-aware modeling.

Protein-ligand binding prediction is central to virtual screening and affinity ranking, two fundamental tasks in drug discovery. While recent retrieval-based methods embed ligands and protein pockets into Euclidean space for similarity-based search, the geometry of Euclidean embeddings often fails to capture the hierarchical structure and fine-grained affinity variations intrinsic to molecular interactions. In this work, we propose HypSeek, a hyperbolic representation learning framework that embeds ligands, protein pockets, and sequences into Lorentz-model hyperbolic space. By leveraging the exponential geometry and negative curvature of hyperbolic space, HypSeek enables expressive, affinity-sensitive embeddings that can effectively model both global activity and subtle functional differences-particularly in challenging cases such as activity cliffs, where structurally similar ligands exhibit large affinity gaps. Our mode unifies virtual screening and affinity ranking in a single framework, introducing a protein-guided three-tower architecture to enhance representational structure. HypSeek improves early enrichment in virtual screening on DUD-E from 42.63 to 51.44 (+20.7%) and affinity ranking correlation on JACS from 0.5774 to 0.7239 (+25.4%), demonstrating the benefits of hyperbolic geometry across both tasks and highlighting its potential as a powerful inductive bias for protein-ligand modeling.