In silico strategies for the selection of chelating compounds with potential application in metal-promoted neurodegenerative diseases

Abstract

The development of new strategies to find commercial molecules with promising biochemical features is a main target in the field of biomedicine chemistry. In this work we present an in silico-based protocol that allows identifying commercial compounds with suitable metal coordinating and pharmacokinetic properties to act as metal-ion chelators in metal-promoted neurodegenerative diseases (MpND). Selection of the chelating ligands is done by combining quantum chemical calculations with the search of commercial compounds on different databases via virtual screening. Starting from different designed molecular frameworks, which mainly constitute the binding site, the virtual screening on databases facilitates the identification of different commercial molecules that enclose such scaffolds and, by imposing a set of chemical and pharmacokinetic filters, obey some drug-like requirements mandatory to deal with MpND. The quantum mechanical calculations are useful to gauge the chelating properties of the selected candidate molecules by determining the structure of metal complexes and evaluating their stability constants. With the proposed strategy, commercial compounds containing N and S donor atoms in the binding sites and capable to cross the BBB have been identified and their chelating properties analyzed.

Ab Initio Design of Chelating Ligands Relevant to Alzheimer’s Disease: Influence of Metalloaromaticity

“…Full geometry optimizations and harmonic frequency calculations were performed using DFT with the nonlocal hybrid B3LYP , functional, a well-tested functional that has been successfully used for a wide variety of systems, including open-shell Cu(II) complexes with saturated coordination environments and similar spin density distributions. − Additionally, our previous study on the chelating properties of different ligands toward Cu(II) and Zn(II) showed good agreement with the observed experimental trends. All calculations were carried out using the following basis sets: For Cu, we used the Watcher’s primitive set (14s9p5d), supplemented with one s, two p, and one d diffuse function and one f polarization function, the final basis set being (15s11p6d1f)/[10s7p4d1f]; for iodine, we used the quasi-relativistic effective core potential (ECP) of Hay and Wadt to represent the innermost electrons and the standard double-ζ LANL2DZ set associated to the ECP for the valence and outermost core orbitals; and for H, C, N, O, and S, we used the standard 6-31++G(d,p) basis set.…”

“…Thermodynamic corrections have been obtained assuming an ideal gas, unscaled harmonic vibrational frequencies, and the rigid rotor approximation by standard statistical methods . Solvation effects were modeled through single-point energy calculations at the same level of theory, with water as solvent, using the self-consistent field polarizable continuum model, COSMO. , To compute the free energy of the [Cu(H 2 O) 4 ] 2+ + 2HL → [Cu(L) 2 ] + 4H 2 O + 2H + reaction in water solution (Δ G sol ), we have followed the strategy adopted by some of us in previous works , using the experimental free energy values for the solvation of water and H + (Δ G Solv(H 2 O) = −6.31 kcal mol –1 and Δ G Solv(H + ) = −265.9 kcal mol –1 , respectively). Because this reaction occurs in solution, the entropy obtained in gas phase was converted from 1 atm to 1 M by subtracting the R ln(V1/V2) cal K –1 mol –1 term to account for the volume change between the two states at 298 K .…”

Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease

“…Compound-(E)- N 1, N 1-Dimethyl- N 4-(pyridin-2-ylmethylene)benzene-1,4-diamine has been shown to modulate reactive oxygen species (ROS) production, metal-induced Aβ aggregation, and neurotoxicity in vitro ( Hindo et al, 2009 ). The drug Deferiprone used in treatment of thalassaemia can be taken as lead compound for the development of MTDL for treating AD because it has moderate to strong affinity for iron, copper and zinc, and low molecular weight makes it easily to modified into multi-functional active molecule ( Rodríguez-Rodríguez et al, 2011 ). The study suggested that Aβ aggregation is inverted in the occurrence of Cu +2 and Zn +2 chelators.…”

Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro models

“…34,35,37 Traditionally, numerous studies have demonstrated that the prediction of drug passage into the CNS via passive diffusion can be estimated using a simple relationship, which establishes the crucial role of polarity and hydrogen bonding capability. 20,54 The reported log BB values, 20 summarized in Table 1, are based on computationally derived physicochemical descriptors such as the calculated octanol-water partition coefficient (c log P) and the topological surface area (TPSA). 20,54 The reported log BB values, 20 summarized in Table 1, are based on computationally derived physicochemical descriptors such as the calculated octanol-water partition coefficient (c log P) and the topological surface area (TPSA).…”