Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Abstract

SARS-CoV-2 is the causative agent of coronavirus(known as , the virus causing the current pandemic. there are ongoing researches to develop effective therapeutics and vaccines against COVID-19 using various methods, and many results have been published.The structure-based drug design of SARS-CoV-2 related proteins is promising. However, 2 reliable information regarding the structural and intra-and intermolecular interactions is required. We have conducted studies based on the fragment molecular orbital (FMO) method for calculating the electronic structure of protein complexes and analyzing their quantitative molecular interactions. This enables us to extensively analyze the molecular interactions in residues or functional group units acting inside protein complexes. Such precise interaction data are available in the FMO database (FMODB) (https://drugdesign.riken.jp/FMODB/). Since April 2020, we have performed several FMO calculations on the structures of SARS-CoV-2 related proteins registered in the Protein Data Bank. We have published the results of 681 structures, including three structural proteins and eleven nonstructural proteins, on the COVID-19 special page (as of June 8, 2021). In this paper, we describe the entire COVID-19 special page of FMODB and discuss the calculation results for various proteins. These data not only aid the interpretation of experimentally determined structures but also the understanding of protein functions, which is useful for rational drug design for COVID-19.

Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir (Xocova) Compared with Its Initial Screening Hit

“…The contributions of the interactions were not only electrostatic interactions and hydrogen bonds but also π-orbital interactions (π-π, CH/π, NH/π, OH/π, and lone pair/π), halogen bonds, and interactions unique to quantum chemical calculations 26,35,36 . Compared to our previous results 21 of clustering the FMO-based interaction energies between 110 ligand complex structures registered by PDB, ensitrelvir more effectively utilizes multiple pockets of S1', S1, and S2 in its molecular recognition to M pro . It also confirmed that ensitrelvir acquired more amino acid residues and interactions than GC376 (PDB ID: 6WTT, FMODB ID: 4NVVN) 27,29 , a well-known covalent inhibitor of animal anticoronaviruses.…”

“…Therefore, in this study, we evaluated the interaction energy between the inhibitor and M pro based on quantum chemical calculations using the fragment molecular orbital (FMO) method [8][9][10][11] to investigate the physicochemical factors that enhanced the inhibitory activity in the drug design from this compound 1 to ensitrelvir. Inter-fragment interaction energy (IFIE) analysis based on FMO calculations can identify amino acid residues and functional groups vital for binding proteins and their inhibitors [12][13][14][15][16][17][18][19][20][21] . Furthermore, by the energy decomposition analysis of IFIE, the type and contribution of the interaction can be clarified for electrostatic interaction (ES), exchange repulsion (EX), charge transfer interaction (CT), and dispersion force interaction (DI) [22][23][24][25] .…”

Quantum-Mechanical Structure Optimization of Protein Crystals and Analysis of Interactions in Periodic Systems

“…Proteins form a very important class of compounds of paramount importance for biochemistry. Protein structures are indispensible to drug discovery, including SARS-CoV-2-related research . Although several experimental methods exist for determining protein structure, such as nuclear magnetic resonance (NMR) and X-ray crystallography, collected experimental data are subject to modeling simulations to produce a structure, and due to resolution limitations and crystal disorder, the resulting structure may have missing atoms or atoms with uncertain or inaccurate coordinates.…”