FAR-DPO: Feasibility-Aware and Robust Direct Preference Optimization for Cyclic Peptide Design

Cyclic peptides represent a promising class of therapeutic compounds in modern drug discovery, often offering improved stability and binding affinity. However, the de novo design of cyclic peptides remains challenging because methods must identify pocket-adaptive cyclization patterns and linkage sites while simultaneously controlling drug-relevant properties. This challenge is particularly pronounced for recent generative models trained predominantly on linear peptide data, which may fail to capture cyclization-specific constraints. To address the limitation, we introduce APCyc, a target-aware de novo cyclic peptide generation framework that explicitly models cyclization and jointly optimizes multiple essential physicochemical properties. By using an expanded residue vocabulary and explicitly encoding cyclization-site and linkage-type information, APCyc learns cyclization-aware representations and leverages Bayesian posterior guidance to steer sampling toward cyclic peptides satisfying multiple property objectives. Experimental results demonstrate that our model learns target-dependent cyclization preferences, and enables effective and controllable multi-property optimization for cyclic peptide design. The source code of this paper is available at https://github.com/HKUSTGZ-ML4Health-Lab/APCyc.

Target-conditioned cyclic peptide design requires coordinating interfacial side chains with macrocyclic closure. Existing end-to-end generators concurrently update geometric and chemical variables from noise, assigning residues to disordered coordinates. Meanwhile, predictor-assisted workflows often get stuck in local traps because they lack feedback in the propose-and-filter stage and ignore 3D structural proposals during sequence search. To overcome the drawbacks of these two paradigms, we propose DC-FLOW, a staged generative framework built around Delayed-Coupling Flow Matching. In principle, DC-FLOW postpones sequence and side-chain activation until a target-conditioned backbone takes shape, resolving structural ambiguity before chemical assignment. Then, it feeds delayed activations back into the backbone, achieving co-evolution of backbone geometry and emerging residue identities by coupling their flows. This mechanism enables more reliable macrocyclic closure and favorable interface packing. For predictor-assisted workflows, DC-FLOW supplies 3D proposals with in-trajectory guidance, enabling cascaded test-time scaling to prune redundant backbones and terminate unpromising refinement early. Extensive experiments show that DC-FLOW improves cyclization fidelity, diversity, and interface energetics, substantially increasing the yield of confident cyclic peptide binders under a fixed final-candidate budget. Our code is available at https://github.com/mianqiu00/DCFlow.

Generative models coupled with reinforcement learning (RL), such as REINVENT and PepINVENT, have emerged as a powerful framework for de novo molecular design. During the ideation process these generative frameworks utilize various predictive models as part of the optimization objectives. However, the utility of the predictive models can be limited by their domain of applicability. When RL is used to explore the chemical space with predictive models, it can suggest molecules that lie outside the predictor's domain of applicability. As a result, the predictions may become less reliable, potentially steering designs into high reward but also high uncertainty chemical spaces. This is particularly pronounced for cyclic peptides which show therapeutic promise due to their modifiability and large interaction surfaces but are understudied compared to small molecules. While passive membrane permeation in cyclic peptides has attracted interest, identifying optimal permeable designs remains challenging yet crucial for targeting intracellular sites. We present an RL-guided generative framework that designs permeable cyclic peptides using an uncertainty-aware permeability predictor as the scoring component. To address predictive uncertainty, especially impacted by novel chemistry, we integrate conformal prediction (CP) as our uncertainty quantification method. CP assesses designs based on the calibrated model under a user-defined confidence level. We demonstrate that rewarding generated peptides with CP-informed predictions improves both reliability and efficiency of peptide optimization process. This also discourages exploration outside the predictor's applicability domain. This approach bridges the gap between predictive uncertainty and RL-guided exploration, showing how generative modelling and conformal prediction can be combined for the first time.