In silico analyses of acetylcholinesterase (AChE) and its genetic variants in interaction with the anti-Alzheimer drug Rivastigmine.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite causing great social and economic impact, there is currently no cure for AD. The most effective therapy to manage AD symptoms is based on acetylcholinesterase inhibitors (AChEi), from which rivastigmine presented numerous benefits. However, mutations in AChE, which affect approximately 5% of the population, can modify protein structure and function, changing the individual response to Alzheimer's treatment. In this study, we performed computer simulations of AChE wild type and variants R34Q, P135A, V333E, and H353N, identified by one or more genome-wide association studies, to evaluate their effects on protein structure and interaction with rivastigmine. The functional effects of AChE variants were predicted using eight machine learning algorithms, while the evolutionary conservation of AChE residues was analyzed using the ConSurf server. Autodock4.2.6 was used to predict the binding modes for the hAChE-rivastigmine complex, which is still unknown. Molecular dynamics (MD) simulations were performed in triplicates for the AChE wild type and mutants using the GROMACS packages. Among the analyzed variants, P135A was classified as deleterious by all the functional prediction algorithms, in addition to occurring at highly conserved positions, which may have harmful consequences on protein function. The molecular docking results suggested that rivastigmine interacts with hAChE at the upper active-site gorge, which was further confirmed by MD simulations. Our MD findings also suggested that the complex hAChE-rivastigmine remains stable over time. The essential dynamics revealed flexibility alterations at the active-site gorge upon mutations P135A, V333E, and H353N, which may lead to strong and nonintuitive consequences to hAChE binding. Nonetheless, similar binding affinities were registered in the MMPBSA analysis for the hAChE wild type and variants when complexed to rivastigmine. Finally, our findings indicated that the rivastigmine binding to hAChE is an energetically favorable process mainly driven by negatively charged amino acids.

Trehalose synthesis inhibitor: A molecular in silico drug design.

Infectious diseases are serious public health problems, affecting a large portion of the world's population. A molecule that plays a key role in pathogenic organisms is trehalose and recently has been an interest in the metabolism of this molecule for drug development. The trehalose-6-phosphate synthase (TPS1) is an enzyme responsible for the biosynthesis of trehalose-6-phosphate (T6P) in the TPS1/TPS2 pathway, which results in the formation of trehalose. Studies carried out by our group demonstrated the inhibitory capacity of T6P in the TPS1 enzyme from Saccharomyces cerevisiae, preventing the synthesis of trehalose. By in silico techniques, we compiled sequences and experimentally determined structures of TPS1. Sequence alignments and molecular modeling were performed. The generated structures were submitted in validation of algorithms, aligned structurally and analyzed evolutionarily. Molecular docking methodology was applied to analyze the interaction between T6P and TPS1 and ADMET properties of T6P were analyzed. The results demonstrated the models created presented sequence and structural similarities with experimentally determined structures. With the molecular docking, a cavity in the protein surface was identified and the molecule T6P was interacting with the residues TYR-40, ALA-41, MET-42, and PHE-372, indicating the possible uncompetitive inhibition mechanism provided by this ligand, which can be useful in directing the molecular design of inhibitors. In ADMET analyses, T6P had acceptable risk values compared with other compounds from World Drug Index. Therefore, these results may present a promising strategy to explore to develop a broad-spectrum antibiotic of this specific target with selectivity, potency, and reduced side effects, leading to a new way to treat infectious diseases like tuberculosis and candidiasis.