Quantitative In Silico Analytical Chemistry for Drug Discovery: From Ion-Ion Interaction to COVID-19 Variants Transmissibility and the Binding Inhibitors

Abstract

Since a new coronavirus (COVID-19) was found in December 2019, more than 40 variants have been identified and spread around the world and causing pandemonium. The urgent requirement for new vaccines and drugs has been demanded. Various drug candidates have been screened using computational chemistry methods. The main-flame computer can handle the auto-docking of proteins with various compounds from the data bank; however, we have to consider that amine and carboxy groups should be ionized and the phenolic hydroxy group may be in molecular form. The properties of bio-mimic ion-exchange groups are quantitatively described using simple model ion exchangers docking with analytes whose properties are easily characterized from their structure. Furthermore, the solvent and ion contributions to molecular interaction between the ion-exchange group and an analyte were quantitatively analyzed. The fundamental in silico analysis of molecular interactions between small molecules was expanded to analyze protein and substrate interactions, quantitative analysis of selective enzyme reaction, such as alanine racemase, serine racemase, alcohol dehydrogenase, cinnamyl alcohol dehydrogenase, D-amino acid oxidase, and D-aspartic acid oxidase. Proteins soften their stereo structures, collect various substrates, and tighten the complex structure to metabolize the substrates. Or the substrates tighten the complex structure and freeze the enzyme activity. The ion-ion interaction site is the major substitute recognition center and the enzyme selectivity is related to the electron localization degree. Further study for protein-protein interactions is applied to analyzing COVID-19 transmissibility as the molecular interaction energy value differences. Indeed, the most contributed interaction was ion-ion interaction, and the strength was quantitatively obtained as electrostatic energy value difference. The strongest interaction energy value was obtained between Omicron BA2 S-RBD and ACE-2. In addition, The ideal binding inhibitors of S-RBD with ACE-2 were acidic compounds that should be adsorbed at the S-RBD contact site with ACE-2 but not inhibit ACE-2 activity. The most effective binding inhibitors were ionized-carboxy compounds including natural compounds. Analytical chemistry means the analysis of chemistry. It is not limited only to measurements of amounts and involves analyses of chemical phenomena based on the chemical structures and properties like organic and biochemistry. The basic interaction mechanisms are supposed to be simple, and the selectivity is qualitatively explained as "like dissolves likes". The developed fundamental technical method is described in part in this tutorial review for targeting to understand the COVID-19 mutant's transmissibility and designing the binding inhibitors based on ion-ion interaction.