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arXiv:2604.10487

CovAngelo: A hybrid quantum-classical computing platform for accurate and scalable drug discovery

Linn Evenseth, Kamil Galewski, Witold Jarnicki, Piero Lafiosca, Vyom N. Patel, Grzegorz Rajchel-Mieldzioć, Martin Šimka, Michał Szczepanik, Emil Żak

physics.chem-phphysics.comp-phquant-phSubmitted Apr 12, 2026• Announced Apr 14, 2026• 0 citations
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Abstract

We present a computational platform for modeling chemical reactions in complex molecular environments, focused on ligand-protein binding in drug discovery. The platform implements our new quantum-in-quantum-in-classical (QM/QM/MM) multiscale embedding model that integrates molecular dynamics with a quantum-information-enhanced density matrix embedding theory and quantum chemistry solvers, including explicit solvent. Quantum-information metrics are utilized to generate entanglement-consistent orbitals, enabling a high-accuracy description of strongly correlated regions. The framework supports multiple computational backends, including multi-CPU, NVIDIA multi-GPU architectures, and quantum hardware (IQM, IonQ, IBM) integrated under CUDA-Q, and is designed for compatibility with future fault-tolerant quantum systems. The new platform's capabilities are demonstrated by modeling covalent docking of zanubrutinib to Bruton's tyrosine kinase via a Michael addition mechanism, computing the full reaction energy profiles and energy barriers at a reduced computational cost relative to existing methods. As a 2nd-generation anticancer agent, zanubrutinib serves as a proof of concept for covalent inhibitor discovery. Accurate first-principles reaction barrier estimations provided by our method can contribute to reducing false positive and negative rates in drug discovery pipelines. Scalability is validated through benchmarks on GPU clusters, cloud-based CPU infrastructures. We demonstrate integration with quantum devices (up to 20 qubits), alongside resource estimates for fault-tolerant quantum computing, indicating potential speedups of up to 20x. Beyond single reactions, the platform supports the construction of reaction networks in chemical metric space, facilitating ligand screening and systematic exploration of reactive pathways.

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We present a computational platform for modeling chemical reactions in complex molecular environments, focused on ligand-protein binding in drug discovery. The platform implements our new quantum-in-quantum-in-classical (QM/QM/MM) multiscale embedding model that integrates molecular dynamics with a quantum-information-enhanced density matrix embedding theory and quantum chemistry solvers, including explicit solvent. Quantum-information metrics are utilized to generate entanglement-consistent orbitals, enabling a high-accuracy description of strongly correlated regions. The framework supports multiple computational backends, including multi-CPU, NVIDIA multi-GPU architectures, and quantum hardware (IQM, IonQ, IBM) integrated under CUDA-Q, and is designed for compatibility with future fault-tolerant quantum systems. The new platform's capabilities are demonstrated by modeling covalent docking of zanubrutinib to Bruton's tyrosine kinase via a Michael addition mechanism, computing the full reaction energy profiles and energy barriers at a reduced computational cost relative to existing methods. As a 2nd-generation anticancer agent, zanubrutinib serves as a proof of concept for covalent inhibitor discovery. Accurate first-principles reaction barrier estimations provided by our method can contribute to reducing false positive and negative rates in drug discovery pipelines. Scalability is validated through benchmarks on GPU clusters, cloud-based CPU infrastructures. We demonstrate integration with quantum devices (up to 20 qubits), alongside resource estimates for fault-tolerant quantum computing, indicating potential speedups of up to 20x. Beyond single reactions, the platform supports the construction of reaction networks in chemical metric space, facilitating ligand screening and systematic exploration of reactive pathways.
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Predicting chemical reactions in biomolecules is challenging because reactive centers are embedded within complex environments that strongly influence their energetics and mechanisms. Here, we present a hybrid quantum-classical workflow that combines molecular dynamics, density functional theory, and correlated wavefunction methods, tightly integrating CPUs, GPUs, and quantum processing units (QPUs) to enable simulations across multiple length and accuracy scales. We apply this approach to ADGRG1 autoproteolysis, a maturation reaction in an adhesion G protein-coupled receptor that has not previously been studied using correlated electronic-structure methods. Our simulations treat a biologically realistic system containing more than one million atoms, including the full-length uncleaved receptor embedded in an endoplasmic-reticulum membrane, while incorporating a 54-qubit IQM quantum processor and up to 1,200 NVIDIA H100 GPUs. These results demonstrate how quantum computers can serve as accelerators within scalable scientific workflows, extending correlated electronic-structure methods to biologically relevant systems.
Accurate prediction of binding affinities and efficient lead optimization remain central challenges in computational drug discovery, particularly for complex biological targets characterized by rugged energy landscapes, conformational heterogeneity, and high-dimensional interaction spaces. Classical computational methods—such as molecular docking, force-field–based simulations, and deep learning models—have made substantial progress, yet they often struggle to capture quantum-mechanical effects and long-range correlations critical to molecular recognition. This study explores a quantum-enhanced framework that integrates Variational Quantum Algorithms (VQAs), quantum-inspired Hamiltonian modeling, and hybrid quantum–classical optimization workflows to improve the fidelity and scalability of drug discovery pipelines. By encoding molecular interactions into parameterized quantum circuits, the framework leverages quantum superposition and entanglement to explore complex chemical space more efficiently, enabling refined estimation of binding energies and accelerated identification of high-quality leads. Preliminary simulations indicate that VQA-based estimators outperform classical baselines for challenging protein–ligand systems, reducing prediction error while maintaining computational tractability. These findings highlight the emerging potential of quantum technologies to enable more accurate, data-efficient, and mechanistically grounded drug discovery for next-generation therapeutics.
Integrating quantum mechanics into drug discovery marks a decisive shift from empirical trial-and-error toward quantitative precision. However, the prohibitive cost of ab initio molecular dynamics has historically forced a compromise between chemical accuracy and computational scalability. This paper identifies the convergence of High-Performance Computing (HPC), Machine Learning (ML), and Quantum Computing (QC) as the definitive solution to this bottleneck. While ML foundation models, such as FeNNix-Bio1, enable quantum-accurate simulations, they remain tethered to the inherent limits of classical data generation. We detail how High-Performance Quantum Computing (HPQC), utilizing hybrid QPU-GPU architectures, will serve as the ultimate accelerator for quantum chemistry data. By leveraging Hilbert space mapping, these systems can achieve true chemical accuracy while bypassing the heuristics of classical approximations. We show how this tripartite convergence optimizes the drug discovery pipeline, spanning from initial system preparation to ML-driven, high-fidelity simulations. Finally, we position quantum-enhanced sampling as the beyond GPU frontier for modeling reactive cellular systems and pioneering next-generation materials.
The exorbitant costs, protracted timelines, and elevated attrition rates associated with traditional drug-discovery pipelines underscore the pressing necessity for computational frameworks that can elucidate biomolecular interactions with quantum-level precision and practical scalability. This study introduces a Hybrid Quantum Classical (HQC) framework that combines quantum variational algorithms, classical molecular dynamics, and quantum-assisted machine-learning optimization into a single drug-screening workflow. It builds on the basic idea of Quantum Molecular Simulation (QMS). In the suggested design, quantum processors are used to selectively fix high-fidelity electronic interactions in reactive binding sites, while classical engines model the large-scale conformational dynamics of biomolecular environments. An adaptive quantum-machine-learning layer speeds up convergence even more by learning how structure and energy are related from quantum-refined descriptors. Benchmark tests against oncogenic targets like EGFR, BCR-ABL1, and p53 show that our method is up to 27% more accurate at converging binding energy and takes 4.3 times less time to compute than standard density-functional-theory and standalone QMS methods. The HQC framework makes quantum drug simulation possible for real-world drug discovery by reducing the limitations of current quantum hardware while keeping electronic-scale accuracy. This study demonstrates that hybrid quantum-classical modeling is a scalable and hardware-compatible approach for advancing next-generation computational drug design and precision therapeutics.
High Resolution Image Download MS PowerPoint Slide Targeted covalent inhibitors represent a promising class of drugs that form specific chemical bonds with their biological targets. There are a multitude of molecular systems where covalent inhibitors could address human health challenges. A high-level quantum chemical description of the formation of the critical covalent bond could provide new mechanistic detail and insights into how the mechanism is influenced by the surrounding biomolecular environment. However, accurately simulating the reactivity and binding specificity of such inhibitors remains a significant challenge. By leveraging advances in quantum computing hardware and algorithms, we discuss how quantum computing could benefit the design of targeted covalent inhibitors and enable more accurate simulations of protein–ligand interactions and accelerate de novo drug discovery.