arXiv subjects

Michał Szczepanik

Publications and source records attributed to Michał Szczepanik.

3 recordsLinked to original sources

arXiv2026

BCover: An Electronic Structure-Based Scoring Suite for Reaction-Aware Covalent Docking

Covalent virtual screening requires ranking compounds according to both noncovalent recognition and their ability to adopt a reaction-competent geometry with an appropriately reactive warhead. Here, we introduce BCover, a reaction-aware scoring suite that combines pre-reactive docking with quantum-chemistry-derived ligand reactivity descriptors, the electrostatic properties of the protein pocket. Quantum-chemical descriptors are aggregated using a nonlinear tree-based scoring model. BCover was evaluated retrospectively on the COValid benchmark, comprising nine targets and ten reactive sites, and compared with AutoDock, DOCK6, DOCKovalent, AlphaFold3 with Rosetta rescoring, and AlphaFold3 confidence-based ranking. BCover achieved an average adjusted LogAUC of 31% (57% max), an average ROC-AUC of 0.88 (0.96 max), an average EF1 of 18 (33 max). Its average LogAUC exceeded those of the classical docking methods and AlphaFold3-Rosetta, although AlphaFold3-mPAE provided the strongest overall enrichment. At an average runtime of about 10~s per ligand, BCover was approximately 25-fold faster than the evaluated AlphaFold3 workflows and achieved the highest average time-adjusted virtual-screening productivity index. Redocking experiments further showed that the method recovered near-native ligand conformations. These results demonstrate that combining docking-derived geometry with ligand local electronic reactivity and pocket electrostatics provides an efficient and interpretable strategy for covalent ligand prioritization. BCover is intended as a high-throughput screening method that complements more computationally demanding QM/MM and free-energy calculations during subsequent lead optimization.

physics.chem-ph↗

arXiv2026

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

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.

physics.chem-ph↗

arXiv2026

Simulating high-accuracy nuclear motion Hamiltonians using discrete variable representation and Walsh-Hadamard QROM on fault-tolerant quantum computers

We present a quantum algorithm for simulating rovibrational Hamiltonians on fault-tolerant quantum computers. The method integrates exact curvilinear kinetic energy operators and general-form potential energy surfaces expressed in a hybrid finite-basis/discrete-variable representation. The Hamiltonian is encoded as a unitary quantum circuit using a quantum read-only memory construction based on the Walsh-Hadamard transform, enabling high-accuracy quantum phase estimation of rovibrational energy levels and dynamics simulations. Our technique provides asymptotic reductions in both logical qubit count and T-gate complexity that are exponential in the number of atoms and at least polynomial in the total Hilbert-space size, relative to existing block-encoding techniques based on linear combinations of unitaries and variational basis representation. Compared with classical variational methods, it offers exponential memory savings and polynomial reductions in time complexity. The quantum volume required for computing the rovibrational spectrum of water can be reduced by up to 100 000 times compared with other quantum methods, increasing to at least 1 million for a classically intractable 30-dimensional (12-atom) molecular system. For this case with a six-body coupled potential, estimating spectroscopic-accuracy energy levels would require about three months on a 1 MHz fault-tolerant quantum processor with fewer than 300 logical qubits, versus over 30 000 years on the fastest current classical supercomputer. These estimates are approximate and subject to technological uncertainties, and realizing the asymptotic advantage will require substantial quantum resources and continued algorithmic progress.

quant-ph↗