Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds - A Computational "Proof-of-Concept".

Over the years, numerous synthetic approaches have been utilized in drug design to improve the pharmacological properties of naturally derived compounds and most importantly, minimize toxic effects associated with their transition to drugs. The reduction of complex bioderived compounds to simpler bioactive fragments has been identified as a viable strategy to develop lead compounds with improved activities and minimal toxicities. Although this 'reductive' strategy has been widely exemplified, underlying biological events remain unresolved, hence the unanswered question remains how does the fragmentation of a natural compound improve its bioactivity and reduce toxicities? Herein, using a combinatorial approach, we initialize a computational "proof-of- concept" to expound the differential pharmacological and antagonistic activities of a natural compound, Anguinomycin D, and its synthetic fragment, SB640 towards Exportin Chromosome Region Maintenance 1 (CRM1). Interestingly, our findings revealed that in comparison with the parent compound, SB640 exhibited improved pharmacological attributes, while toxicities and off-target activities were relatively minimal. Moreover, we observed that the reduced size of SB640 allowed 'deep access' at the Nuclear Export Signals (NES) binding groove of CRM1, which favored optimal and proximal positioning towards crucial residues while the presence of the long polyketide tail in Anguinomycin D constrained its burial at the hydrophobic groove. Furthermore, with regards to their antagonistic functions, structural inactivation (rigidity) was more pronounced in CRM1 when bound by SB640 as compared to Anguinomycin D. These findings provide essential insights that portray synthetic fragmentation of natural compounds as a feasible approach towards the discovery of potential leads in disease treatment.