Binding interactions and in silico ADME prediction of isoconessimine derivatives as potent acetylcholinesterase inhibitors.

In pursuit of new acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease (AD), a series of ten previously synthesized isoconessimine compounds (7a-7j) was in silico investigated for their binding interactions with AChE and pharmacokinetics based on absorption, distribution, metabolism, and excretion (ADME) properties using molecular docking, ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) method and SwissADME tools. Docking experiments showed that all compounds bind within the active site gorge of AChE (PDB entry 1C2B), posing its aryloxy-substitutional ethyl group to catalytic site and conessine skeleton to peripheral anionic site. ONIOM interaction energy was used as an ONIOM score to improve docking score, and it ranked 7b as the most potent AChE inhibitor, in agreement with previous experiment. Residues, ASP74, TRP86, GLY122, GLU202, TRP286, GLU292, SER293, ILE294, TYR337, TYR341, and HIS447 were identified as important for the binding of the AChE-isoconessimine complex. The SwissADME investigation suggested that four compounds (7a, 7c, 7d and 7f) agree with the rules of drug-likeness. The steric and electronic effects on the aryloxy-substitutional ethyl group as important factors in the AChE inhibition were also discussed, which brings a better understanding of Alzheimer's disease drug development.

Improved scFv anti-HIV-1 p17 binding affinity guided from the theoretical calculation of pairwise decomposition energies and computational alanine scanning.

Computational approaches have been used to evaluate and define important residues for protein-protein interactions, especially antigen-antibody complexes. In our previous study, pairwise decomposition of residue interaction energies of single chain Fv with HIV-1 p17 epitope variants has indicated the key specific residues in the complementary determining regions (CDRs) of scFv anti-p17. In this present investigation in order to determine whether a specific side chain group of residue in CDRs plays an important role in bioactivity, computational alanine scanning has been applied. Molecular dynamics simulations were done with several complexes of original scFv anti-p17 and scFv anti-p17mutants with HIV-1 p17 epitope variants with a production run up to 10 ns. With the combination of pairwise decomposition residue interaction and alanine scanning calculations, the point mutation has been initially selected at the position MET100 to improve the residue binding affinity. The calculated docking interaction energy between a single mutation from methionine to either arginine or glycine has shown the improved binding affinity, contributed from the electrostatic interaction with the negative favorably interaction energy, compared to the wild type. Theoretical calculations agreed well with the results from the peptide ELISA results.

Pairwise decomposition of residue interaction energies of single chain Fv with HIV-1 p17 epitope variants.

Computational assisted modeling was carried out to investigate the importance of specific residues in the binding site of scFv. In this study, scFv against HIV-1 epitope at the C-terminal on p17 (scFv anti-p17) was used as a candidate molecule for evaluating the method. The wild-type p17 and its nine natural mutants were docked with scFv anti-p17. Potential mean force (PMF) scores predicted the most favorable binding interaction, and the correlation agreed well with the corresponding activity data from the peptide based ELISA. In the interaction with solvent molecules, the 3D structures of scFv anti-p17 and selected peptide epitopes were further investigated by molecular dynamics (MDs) simulation with the AMBER 9 program. Post-processing of the snapshot at equilibrium was performed to evaluate the binding free energy and pairwise decomposition or residue-based energy calculation of complexes in solution using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) protocol. Our results demonstrated that the specific residues located in the complementary determining regions (CDRs) of scFv anti-p17, MET100, LYS101, ASN169, HIS228, and LEU229, play a crucial role in the effective binding interaction with the absolute relative decomposed energy more than 2.00 kcal/mol in comparison to the original substrate.