69 research outputs found
Application of singular value decomposition to the inter-fragment interaction energy analysis for ligand screening
We evaluated the binding affinity between p38 MAP kinase and various inhibitors through use of the fragment molecular orbital (FMO) method at MP2/6-31G* level in comparison to experimental values of half maximal inhibitory concentration (IC50). Initially, the calculated results of the FMO-IFIE (inter-fragment interaction energy) sums for 60 complex structures registered in the Protein Data Bank were not well correlated with the IC50 activity data. Therefore, we performed the singular value decomposition (SVD) for the calculated results of the IFIE matrix (amino acid residues x various ligands) to improve the correlation and determine the cause of the initial poor results. In SVD, the original matrix is divided into multiple vectors that are orthogonal to each other. Through this method, we improved the correlation by removing some particular vectors that involved noise components and impaired the correlation. In addition, the correlation between the IC50 and FMO-IFIE for 22 complex structures of estrogen receptor α (Erα) was also improved in this way. We analyzed the amino acid residues of receptors that were mainly involved in the removed vectors and found an overestimation of the strength of the hydrogen bond between glutamic acid and the ligand
Intermolecular Interaction Among Remdesivir, RNA and RNA-Dependent RNA Polymerase of SARS-CoV-2 Analyzed by Fragment Molecular Orbital Calculation
COVID-19,
a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from
Wuhan, China, has now spread around the world, triggering a global pandemic,
leaving the public eagerly awaiting the development of a specific medicine and
vaccine. In response, aggressive efforts are underway around the world to
overcome COVID-19. In this study, referencing the data published on the Protein
Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the
interaction between the complex structures of the RNA-dependent RNA polymerase
(RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum
chemical perspective based on the fragment molecular orbital (FMO) method. In
addition to the hydrogen bonding and intra-strand stacking between
complementary strands as seen in normal base pairs, Remdesivir bound to the
terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking
with the -1A base of the complementary strand and an additional hydrogen bond
with an intra-strand base, due to the effect of chemically modified functional
group. Moreover, stable OH/π interaction is also formed with Thr687 of the
RdRp. We quantitatively revealed the exhaustive interaction within the complex among
Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results
in the FMODB database.</p
Physicochemical Properties and Transdermal Absorption of a Flurbiprofen and Lidocaine Complex in the Non-Crystalline Form
Amorphous drug formulations exploiting drug–drug interactions have been extensively studied. This study aims to develop a transdermal system containing an amorphous complex of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen (FLU) and lidocaine (LDC) for alleviating chronic pain. The high-viscosity complex between FLU and LDC (Complex) was obtained by heating in ethanol. For the complex, attenuated total reflection-Fourier transform infrared spectroscopy showed a shift in the carboxy-group-derived peak of FLU, and differential scanning calorimetry indicated the endothermic peaks associated with the melting of FLU and LDC disappeared. 13C dipolar decoupling and 15N cross-polarization magic-angle spinning nuclear magnetic resonance measurement suggested the interaction between the carboxyl group of FLU and the secondary amine of LDC. The interaction between the aromatic rings of FLU and LDC contributed to the molecular complex formation. The solubility of FLU from the complex was about 100 times greater than FLU alone. The skin permeation flux of FLU from the complex through the hairless mouse skin was 3.8 times higher than FLU alone in hypromellose gel. Thus, adding LDC to the formulation can be an effective method for enhancing the skin permeation of NSAIDs, which can prove useful for treating chronic pain and inflammatory diseases
Explicit solvation of a single-stranded DNA, a binding protein, and their complex: a suitable protocol for fragment molecular orbital calculation
Interaction between a Single-Stranded DNA and a Binding Protein Viewed by the Fragment Molecular Orbital Method
Molecular Recognition of SARS-CoV-2 Spike Glycoprotein: Quantum Chemical Hot Spot and Epitope Analyses
Due to the COVID-19 pandemic, researchers have attempted to identify complex structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S-protein) with angiotensin-converting enzyme 2 (ACE2) or a blocking antibody. However, the molecular recognition mechanism - critical information for drug and antibody design - has not been fully clarified at the amino acid residue level. Elucidating such a microscopic mechanism in detail requires a more accurate molecular interpretation that includes quantum mechanics to quantitatively evaluate hydrogen bonds, XH/π interactions (X = N, O, and C), and salt bridges. In this study, we applied the fragment molecular orbital (FMO) method to characterize the SARS-CoV-2 S-protein binding interactions with not only ACE2 but also the B38 Fab antibody involved in ACE2-inhibitory binding. By analyzing FMO-based interaction energies along a wide range of binding inter-faces carefully, we identified amino acid residues critical for molecular recognition between S-protein and ACE2 or B38 Fab antibody. Importantly, hydrophobic residues that attribute to weak interactions such as CH-O and XH/π interactions, as well as polar residues that construct conspicuous hydrogen bonds, play important roles in molecular recognition and binding ability. Moreover, through these FMO-based analyses, we also clarified novel hot spots and epitopes that had been overlooked in previous studies by structural and molecular mechanical approaches. Altogether, these hot spots/epitopes identified between S-protein and ACE2/B38 Fab antibody may provide useful information for future anti-body design and small or medium drug design against the SARS-CoV-2. </div
- …