Will perplexity prevail over complexity in biomedical natural products research?

The inherently complexity of bioactive natural products (NPs) requires new analytical technology, trans-disciplinary approaches, and an integrative pharmacognosy approach for advancement. Recent research reveals that complexity comes in three main flavors: obvious, less obvious, and residual. While analytical chemistry and (bio)synthetic biology progress renders chemodiversity an obvious complexity, other chemistry aspects are less obvious: mechanistic explanations for postulated “botanical synergy” are mostly elusive; monomers w/well-understood 3D (stereo)chemistry of (±)-catechin overwhelms analytical tools and analysist building SARs of 30,000+ perceivable tetrameric grape seeds tannins. As Nature’s permutations outstrip scientific capabilities, perplexity prevails over complexity when developing rationales for synthesis/isolation of promising analogues and pharmacophore definition. Correlating ClpC1-target interaction with anti-M.tb. bioactivity profiles of rufomycin anti-TB leads exemplify less obvious complexity. Despite being an obvious complexity, impurity ranks high among factors that confound NP research. Searches for bioactives (phytoestrogens, antimicrobials) frequently lead to residuals explaining the bioactivity of crude NPs: finding that 0.24% within a “pure” NP explain the entire anti-M.tb. “lead” potential was a perplexing demonstration of residual complexity. Apparent simplicity of hyper-popular NPs hide the less obvious and residual complexity of their promiscuous properties. Well-founded rationales that designate NPs such as curcumin as invalid/improbable panaceas (IMPs) are less complex than the impact of basic tenets of pharmacognosy, scientific publishing, or marketing practices. Advertised globally, the therapeutic potentials ascribed to IMPs are in perplexing contrast to the rigor of available efficacy evaluations. The present contribution structures the three complexity flavors and identifies approaches for overcoming perplexity in NP research.