Paradigms and paradoxes: Mechanisms for possible enhanced biological activity of bilaterally symmetrical chemicals

Abstract

We propose a mechanism that bilateral symmetry yields an entropic advantage for enzyme recognition. We suggest that bilateral symmetry may be a guiding principle used by nature to produce some particularly effective receptor-ligand interactions. An essential result is that bilateral symmetry is common among enzyme inhibitors, which coupled with an enhanced bond energy that connects dimer molecules compared to a reduced bond energy profile for higher oligomers provides a clue to explain the abundance of bilaterally symmetrical molecules found in Nature. Keywords Molecular bilateral symmetry . Enzyme recognition . Receptor-ligand interactionsRecent interest has focused on natural product bilateral symmetry and the prediction of selectivity of dimeric molecules by density functional theory (DFT) and semiempirical calculations [1]. It has been shown that bilateral symmetry [defined as including C 2 (sigma mirror or rotation axis), C s , and C 2v point groups in molecules] is present in a number of natural product structures. Dimeric natural products were found to evolve more energy per connection than the corresponding trimers or tetramers. The assumption of maximization of interaction energy suggests the corollary

Virtual Ligand Screening of the National Cancer Institute (NCI) Compound Library Leads to the Allosteric Inhibitory Scaffolds of the West Nile Virus NS3 Proteinase

“…For example, natural compounds with bilateral symmetry are more frequently enzyme inhibitors (22%) in comparison with nonsymmetrical natural compound (8%). 32 The inhibitory characteristics of the scaffolds we identified are comparable with those selected by others. The existing WNV and DV NS2B-NS3 inhibitors are predominantly peptide based and they target directly the active site of the NS3pro domain.…”

Biosynthesis of Himastatin: Assembly Line and Characterization of Three Cytochrome P450 Enzymes Involved in the Post‐tailoring Oxidative Steps

“…Our interest to study the biosynthesis of 1 was inspired by its intriguing structural features, which hinted that it is biosynthesized by a nonribosomal peptide synthetase (NRPS) assembly line, followed by post‐NRPS modifications including oxygenation of the L ‐Trp residue to a hexahydropyrroloindole subunit and subsequent symmetrical biaryl coupling. Many complex natural products are symmetric dimers formed through a biaryl linkage, usually biologically superior to those of their monomers 8. Enzymes involved in biaryl natural product formation through oxidative phenol coupling have been reported;9 however, the exact enzymatic reaction catalyzing this regioselective oxidative carbon–carbon coupling reaction is poorly understood.…”

Biosynthesis of Himastatin: Assembly Line and Characterization of Three Cytochrome P450 Enzymes Involved in the Post‐tailoring Oxidative Steps

“…Many complex natural products are symmetric dimers formed through a biaryl linkage, usually biologically superior to those of their monomers. [8] Enzymes involved in biaryl natural product formation through oxidative phenol coupling have been reported; [9] however, the exact enzymatic reaction catalyzing this regioselective oxidative carbon-carbon coupling reaction is poorly understood. The aims of this study are to elucidate the biosynthetic pathway of 1, and to delineate the enzymology of the exciting chemical transformations of the aforementioned unique structural characteristics.…”