SurfSpec is a lead‑optimization framework that improves drug specificity without needing off‑target structures. By measuring and reducing the geometric mismatch between a ligand and its target pocket, SurfSpec provides a conservative lower bound on specificity against geometrically separated off‑target pockets. The method iteratively grows ligands toward under‑occupied target surface patches, alternating between linker generation and refinement, and demonstrates superior empirical specificity on the CrossDocked2020 test set while maintaining competitive target affinity.
arXiv:2606. 00555v1 Announce Type: new Abstract: Structure-based drug design increasingly employs LLM agents to iteratively refine ligands against a target pocket, yet a viable ligand must satisfy two often-conflicting objectives -- binding affinity and druggability -- which single optimization steps rarely improve together.
By Zaifei Yang, Weiyu Chen, Yaqing Wang, James Kwok
Drug discovery and development is time-consuming and resource-intensive, motivating computational approaches such as diffusion models for de novo drug design. Many such models follow the structure-based drug design (SBDD) paradigm, generating molecules to fit a target binding pocket.
FuseDiff is an end‑to‑end diffusion model designed for dual‑target structure‑based drug design, jointly generating a ligand graph and two pocket‑specific binding poses conditioned on both target pockets. It employs a message‑passing backbone with Dual‑target Local Context Fusion (DLCF) to fuse ligand atom contexts from both pockets, preserving symmetry while enabling expressive joint modeling. The model enforces topological consistency across the two poses and allows target‑specific geometric adaptation, achieving state‑of‑the‑art docking performance and enabling systematic assessment of dual‑target pose quality before docking‑based pose search.
By Jianliang Wu, Anjie Qiao, Zhen Wang, Zhewei Wei, Sheng Chen
The paper introduces ReGeoDTA, a framework that preserves chemical heterogeneity and continuous geometric relationships in drug and protein representations to improve drug–target affinity prediction. Experiments on three benchmark datasets show that maintaining representation fidelity consistently enhances predictive accuracy across various DTA architectures, while degrading representations harms performance and cannot be recovered by more complex downstream models. The study highlights representation fidelity as a key upstream design principle for accurate and generalizable affinity prediction.
By Yixiao Li, Yining Qian, Yefan Chen, Zenghui Chen, Jiayue Sun, Yuhai Zhao, Cheng Tan, An-Yang Lu
arXiv:2608. 11483v1 Announce Type: new Abstract: Hit-to-lead optimization requires iterative design of hit analogs across competing potency, selectivity, physicochemical, pharmacokinetic, safety, and synthetic constraints.
By Kelvin P. Idanwekhai, Enes Kelestemur, Benjamin Strickland, Matthew Hart, Steini Davidsson, Angelos Angelopoulos, Ron Alterovitz, Marcello DeLuca, Alexander Tropsha