Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies

Abstract

The identification of BACE-1, a key enzyme in the production of Amyloid-β (Aβ) peptides, generated by the proteolytic processing of amyloid precursor protein, was a major advance in the field of Alzheimer's disease as this pathology is characterized by the presence of extracellular senile plaques, mainly comprised of Aβ peptides. Hydroxyethylamines have demonstrated a remarkable potential, like candidate drugs, for this disease using BACE-1 as target. Density Functional Theory calculations were employed to estimate interaction energies for the complexes formed between the hydroxyethylamine derivated inhibitors and 24 residues in the BACE-1 active site. The collected data offered not only a general but a particular quantitative description that gives a deep insight of the interactions in the active site, showing at the same time how ligand structural variations affect them. Polar interactions are the major energetic contributors for complex stabilization and those ones with charged aspartate residues are highlighted, as they contribute over 90% of the total attractive interaction energy. Ligand-ARG296 residue interaction reports the most repulsive value and decreasing of the magnitude of this repulsion can be a key feature for the design of novel and more potent BACE-1 inhibitors. Also it was explained why sultam derivated BACE-1 inhibitors are better ones than lactam based. Hydrophobic interactions concentrated at S1 zone and other relevant repulsions and attractions were also evaluated. The comparison of two different theory levels (X3LYP and M062X) allowed to confirm the relevance of the detected interactions as each theory level has its own strength to depict the forces involved, as is the case of M062X which is better describing the hydrophobic interactions. Those facts were also evaluated and confirmed by comparing the quantitative trend, of selected ligand-residue interactions, with MP2 theory level as reference standard method for electrostatic plus dispersion energies.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…Thus, designing inhibitors that are capable of forming those vital anchor point interactions with BACE1 and maintaining this interaction over time is crucial to yield the best possible inhibitory activity. It was observed that the protonation status of hydroxyethyl amines could be shifted with time resulting in loss of essential interactions with BACE1 residues shifting the flap confirmation from the active (closed) back to the open form . Therefore, this shift in the flap confirmation can explain how some HEAs derivatives would fail to inhibit the BACE1 activity in real time.…”

Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)

“…These plaques consist of aggregated amyloid--peptide (A ) deposits, -protein aggregation, oxidative stress, dyshomeostasis of biometals, and low acetylcholine (ACh) levels and plays significant role in the pathophysiology of the disease [7]. Nowadays, the most used therapeutic treatment against AD involves the use of acetylcholinesterase inhibitors (AChEIs) that improve AD symptoms by AChE inhibition [8][9][10][11][12]. The reversible AChE inhibition has become the promising target for the treatment of AD which is mainly associated with low in vivo AChE levels.…”

Evaluating the enthalpic contribution to ligand binding using QM calculations: effect of methodology on geometries and interaction energies

“…Alternatively, smaller, approximate models can be used at higher levels of QM theory to evaluate particular regions of interest more rapidly. [41][42][43][44] Each of the methods discussed above offers distinct advantages in particular circumstances. For example, MM methods are very quick to evaluate, meaning extensive sampling is possible.…”

“…A number of methods are available to predict the strength of interaction of individual functional groups which can prove extremely insightful in the design and modification of lead series. 41,43,44,[49][50][51] In this work we consider the use of small QM models of receptors, consisting of the key polar active site interactions, rather than generic probes. The region selected is not as extensive as used in the approach of Gueto-Tettay, who used residues within 5 Å of the active site, which, due to the significant size, necessitates the use of the semi-empirical PM6 method.…”

“…The region selected is not as extensive as used in the approach of Gueto-Tettay, who used residues within 5 Å of the active site, which, due to the significant size, necessitates the use of the semi-empirical PM6 method. 41 Here we investigate smaller, yet more interaction relevant active site models. We are not, per se, interested in predicting the much more challenging absolute binding free energy, 28 rather, the goal is to determine whether such methods could be used to assess the relative interaction strength of inhibitors with key polar elements of a receptor, with the view to using them to rapidly assess alternative modifications of lead series to improve the contribution to enthalpic binding.…”