PSGS-Drug: Generation-Time Dual-Pocket Guidance for Non-Symmetric Dual-Target Molecular Design

Abstract

Generating molecules that jointly fit heterogeneous protein binding environments while retaining medicinal-chemistry plausibility remains challenging in computational dual-target design. We present PSGS-Drug, a generation-time dual-pocket framework that fuses localized token priors from the mitogen-activated protein kinase kinase 1 (MEK1) adenosine triphosphate (ATP)-site context in Protein Data Bank (PDB) entry 7PQV and the FK506-binding protein 12 (FKBP12)-FKBP12-rapamycin-binding (FRB) composite context of mechanistic target of rapamycin (mTOR) in PDB entry 3FAP, and uses contact-guided prefix initialization for rank-head exploration. The selected pair represents pathway-linked but structurally nonsymmetric intervention contexts: the druggable MEK1 ATP site and the mTOR-associated FKBP12-FRB composite interface. Their joint consideration is motivated by documented MEK/ERK–PI3K/AKT/mTOR cross-talk, compensatory resistance, and disease-specific preclinical evidence in NRAS mutant melanoma. [ Mendoza, M. C.; et al.Trends Biochem. Sci.2011, 36, 320–328.Kakadia, S.; et al.Onco Targets Ther.2018, 11, 7095–7107.Posch, C.; et al.Proc. Natl. Acad. Sci. U.S.A.2013, 110, 4015–4020.Mita, M.; et al.Invest. New Drugs2017, 35, 616–626, and.Wang, B.; et al.Oncogene2021, 40, 5590–5599]. Across five independent contact-guided runs standardized to 1889 unique valid molecules, PSGS-Drug achieved a mean summed two-context docking score (docksum) of −17.700 ± 0.242 and 29.00 ± 2.98% coverage of the stated operational dual-hit ≤−9.0 criterion; relative to independently repeated Pocket2Mol and PCMol comparators under the shared downstream protocol, it showed lower full-set docksum and higher operational dual-hit coverage after six-test Holm adjustment, and a five-seed matched A0 to A1 validation on the additional 5L2I-3ERT kinase–nuclear-receptor pair supported transfer of the fused-prior population-level effect. Docking scores, operational dual-hit labels, and residue-level contact analyses are interpreted as fixed-protocol computational prioritization signals that support candidate selection for this pathway-linked dual-context hypothesis. The biochemical and cellular activities of individual candidates remain to be tested; PSGS-Drug is therefore presented as an early stage, limitation-aware computational prioritization framework.