title: [Significance of quantum chemical interactions for medicinal science and design of β-secretase inhibitors].
abstract: This review discusses the importance of quantum chemical interactions in biomolecules for medicinal science and their relevance to the author's β-secretase (BACE1) inhibitor drug discovery research. Although molecular mechanics/dynamics (MM/MD) methods are available in many in silico design tools used for drug discovery, they cannot accurately evaluate quantum effects between biomolecules and drugs. The key roles of biomolecular quantum chemical interactions in drug discovery are discussed using the arginine side chain as an example. Arginine is recognized as a charged amino acid in commonly used drug design software, unlike other amino acids with π-electron orbitals, such as phenylalanine, tyrosine, and tryptophan. Quantum chemical interactions via the arginine side chain are crucial for molecular recognition, and are found in many X-ray crystal structures, such as protein-protein, protein homodimer, RNA aptamer-protein, and enzyme-inhibitor complexes. This review describes the essential role of quantum chemical interactions via the arginine side chain in the mechanism of BACE1 inhibition, and proposes an "electron donor/acceptor bioisostere" concept for medicinal science based on quantum chemical interactions. Several potent BACE1 inhibitors, as well as the first peptides with BACE1 inhibiting activity were designed and synthesized based on studies of quantum chemical interactions via arginine side chain and the "electron donor bioisostere" concept.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004583:Electrons; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007930:Leucine; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D001120:Arginine; D053829:Amyloid Precursor Protein Secretases; D007930:Leucine