Number Of Polar Atoms Research Articles

Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includes cholinergic deficit among its main causes. Following a multi-target design strategy, the structure of the approved drug donepezil was taken as the starting point for generating some new potential multi-functional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayed against three different enzymes, namely the well-established targets acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studies confirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalytic anionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, which revealed that the inhibition potency seems to depend upon the length of the spacer and the number of polar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated. Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools. Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-target directed agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent and selective AChE inhibitor (IC50 = 0.8 nM) than donepezil, besides being able to bind bivalent copper cations (pCu = 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did not show significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 μM) in a MTT assay.

Drug-like Properties and Fraction Lipophilicity Index as a combined metric.

Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs. The FLI and FLI-C (ClogP based FLI) drug-like range covers 92 % and 91 % of class 1 drugs, respectively. Using MlogP, a narrower drug-like FLI-M range 0-7 was established, covering 91 % of class 1 drugs. The dependence of the degree of ionization to intrinsic lipophilicity within the FLI (FLI-C, FLI-M) drug-like range as well as the inter-relation between the other Ro5 properties (Mw, HD, HA) was explored to define drug-like / non-drug-like combinations as a safer alternative to single properties for drug candidates’ prioritization. In this sense, we propose a combined metric of Mw and the number of polar atoms (Mw/NO) to account for both size and polarity. Setting the value 50 as cutoff, a distinct differentiation between class 1 and class 2 drugs was obtained with Mw/NO>50 for more than 70 % of class 1 drugs, while the opposite was observed for class 2 drugs.

The influences of surface polar unit density on the water dispersity of nanoparticles

The impacts of surface polar unit density on the water dispersity of nanoparticles have been investigated using molecular dynamics simulations. The nanoparticles with various polar unit densities were designed by assigning partial charges on different numbers of surface atoms of C60s. The water dispersity of the nanoparticle is enhanced rapidly as the introduction of surface polar atoms. Nevertheless, when the number of polar atoms (N) grows beyond a certain value, the change in the nanoparticle's water dispersity is relatively small. The hydration behaviors of nanoparticles were then studied to investigate the dependence of water dispersity on the surface polar unit density. The introduction of surface polarity enhances the interaction potential between the hydration water and the nanoparticle (Uwater−NP) which should facilitate the dissolution of nanoparticles. On the other hand, the surface polarity also reduces the number of hydrogen bonds formed by a water molecule in the hydration layer with other water molecules (NHB) and enhances the interaction potential between the contacted nanoparticles (UNP−NP) which may hinder their dispersion. However, Uwater−NP, NHB, and UNP−NP all change non-monotonically with N. Moreover, the surface polarity also rearranges the hydration structure of the nanoparticle, which also changes non-monotonically with N. The dependence of the nanoparticle's water dispersity on the surface polar unit density should be attributed to the interplay of different aspects of nanoparticle's hydration behavior, especially the interplay of Uwater−NP, UNP−NP, and NHB.

Ligand efficiency indices for an effective mapping of chemico-biological space: the concept of an atlas-like representation

We propose a numerical framework that permits an effective atlas-like representation of chemico-biological space based on a series of Cartesian planes mapping the ligands with the corresponding targets connected by an affinity parameter (K(i) or related). The numerical framework is derived from the concept of ligand efficiency indices, which provide a natural coordinate system combining the potency toward the target (biological space) with the physicochemical properties of the ligand (chemical space). This framework facilitates navigation in the multidimensional drug discovery space using map-like representations based on pairs of combined variables related to the efficiency of the ligands per Dalton (molecular weight or number of non-hydrogen atoms) and per unit of polar surface area (or number of polar atoms).

Entropic trends in aqueous solutions of the common functional groups

While much is known about the properties of small organic molecules in aqueous solution, one quantity that has eluded a detailed understanding is their entropy. Different functional groups interact in diverse ways with water molecules and thereby influence a molecule's solubility, conformation and association behaviour. Experiment can access the total entropy of solvation but struggles to give a more detailed break-down of the entropic components. Established theoretical and computational methods based on perturbation give insight into changes in solute–solvent and solvent–solvent entropy components, but these multibody terms that represent changes are not intuitive to interpret and can be expensive or difficult to evaluate. Partition-function methods, on the other hand, have the capability of determining the entropy of every degree of freedom of every molecule in the system. They do this by determining effective potentials for each degree of freedom, and evaluating the associated entropy component from the partition function of the effective potential. The obstacle to such an approach has been finding a reliable way to define and derive these effective potentials. This we have overcome in a two-fold manner: firstly, the shape of the effective potential for each molecule, which relates to vibrational and librational motion of the confined molecule, is derived from the magnitudes of the forces and torques measured in a molecular dynamics simulation of the solution; secondly, the number of minima for each effective potential, which relates to the number of positions and orientations in solution, is derived from the translational and rotational discretisations by the surrounding solvent molecules. This method has been shown to successfully reproduce the entropy of liquid water and to examine the entropy loss of water around noble-gas solutes. In this work, we extend the approach to reveal the nature of water's entropy around small organic molecules with a range of functional groups. The vibrational and librational entropies of solutes and water decrease for solutes with more polar atoms, as would be expected. The number of solute orientations depends on solute size, whereas the number of water orientations depends on the number of polar atoms in the solute. Solutes are classified according to how their donors and acceptors affect water's orientational entropy. Agreement of the calculated standard Gibbs free energy of solvation with experiment is very good with a mean-unsigned error of 2.5 kJ mol−1, but the entropies and enthalpies, not being negative enough, could be improved with better force fields.

Predicting blood–brain barrier penetration from molecular weight and number of polar atoms

A simple three-descriptor model to predict blood–brain barrier is derived from a training set of 78 compounds: log BB = −9.880 × 10 −6 M W 2 + 7.339 × 10 −3 M W–0.2268 n pol−0.1143 ( n = 78, r 2 = 0.74), where log BB is the logarithm of the ratio of the steady-state concentration of the compound in the brain to concentration in the blood, M W is the molecular weight, n pol is the number of polar atoms (oxygen, nitrogen, and attached hydrogen), n is the number of compounds, and r is the correlation coefficient. The model is validated through use of leave-one-out procedure and an external test set (25 compounds). The model is suitable for the rapid prediction of the blood–brain barrier penetration of drug candidates because of its predictive ability and simplicity.

Multistep Mechanism of Chloride Translocation in a Strongly Anion-Selective Porin Channel

The strongly anion-selective porin channel Omp32 from the bacterium Delftia acidovorans differs from other unspecific porins by its pronounced selectivity for anions and its particularly small channel cross-section. Multinanosecond molecular dynamics simulations of chloride ion movement in this pore protein suggest that translocated anions interact intimately with the charges of a “basic ladder”, whose dynamics lead the anions in a stepwise manner through the constriction zone of the channel. The ladder-steps comprise the central clustered arginine groups and flanking basic residues at its exoplasmic and periplasmic sides. The computed free energy profile of ion movement in and around the constriction zone shows a corresponding succession of free energy minima and barriers. A number of polar atoms from other amino acids contribute to the coordination of Cl − at certain sites and to its temporary immobilization in the channel. A special binding site occurs at the transition of the constriction zone to the periplasmic funnel, binding the chloride ion over significant lengths of time. The results from our MD study offer a possible explanation for the nonlinear conductance properties and unusual salt-dependent characteristics of Omp32 observed earlier in experimental measurements.