Drug-Likeness Beyond Lipinski: Rethinking Natural Product Developability Through Bioavailability, Structural Complexity, Formulation Feasibility, and Safety Logic

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Natural products continue to challenge conventional drug-discovery screening because many structurally rich candidates do not fit comfortably within simplified small-molecule drug-likeness rules, yet rule violation alone does not determine whether a candidate can be developed. This article proposes a conceptual developability framework for natural product candidates that distinguishes heuristic drug-likeness from development-facing decision logic. The framework is constructed through four interacting domains: bioavailability, structural complexity, formulation feasibility, and safety logic. Rather than reducing bioavailability to oral absorption, complexity to molecular burden, formulation to universal rescue, or safety to natural origin, the proposed architecture evaluates whether evidence patterns support progression, conditional optimization, formulation- or route-dependent rescue, evidence-insufficient hold, or deprioritization. The framework emphasizes route-sensitive exposure, interpretable structural behavior, realistic formulation pathways, exposure-dependent safety, and visible uncertainty. Its principal contribution is a structured decision logic that connects heterogeneous evidence to candidate progression without inventing numerical thresholds or collapsing decisions into a single score. The framework is proposed as a conceptual architecture for natural product developability assessment and has not been prospectively validated.