Prediction of the Intrinsic Hydrogen Bond Acceptor Strength of Organic Compounds by Local Molecular Parameters

Abstract

A quantum chemical model has been developed for predicting the hydrogen bond (HB) acceptor strength of monofunctional organic compounds from electronic ground-state properties of the single molecules. Local molecular parameters are used to quantify electrostatic, polarizability, and charge transfer components to hydrogen bonding, employing the ab initio and density functional theory levels HF/6-31G** and B3LYP/6-31G**. The model can handle lone pairs of intermediate and strong HB acceptor heteroatoms (N, O, S) as well as of weak HB acceptor halogens (F, Cl, Br) and includes also olefinic, alkyne, and aromatic pi-bonds as weak HB acceptor sites. The model calibration with 403 compounds and experimental values for the Abraham HB acceptor strength B yielded squared correlation coefficients r(2) around 0.95, outperforming existing fragment-based schemes. Model validation was performed applying a leave-50%-out procedure, yielding predictive squared correlation coefficients q(2) of around 0.95 for the subsets that both cover the whole chemical domain as well as (almost) the whole target value range of the data set.

QM methods in structure based design: Utility in probing protein–ligand interactions

“…QM methods are more accurate than MM based alternatives due to the fact they consider the underlying physics of a given molecular system more precisely [15,[30][31][32][33][34][35]. However, they are rarely used for this purpose due to their perceived high computational demand and the relatively few cases studies reported in the literature.…”

“…This relatively simple approximation has led to the development of in-silico tools using small probe molecules to estimate H-bond strength which can prove very useful in lead optimization efforts [30][31][32][33][34][35]. However, simplifications involved in these models might mask SAR in cases where the generic probes are not fully representative of the receptor, or the effect of the local active site conformation is important.…”

“…They have proved very effective in a wide variety of applications yet it is becoming increasingly clear that these methods may lack the required accuracy to describe the subtleties associated with protein-ligand complexes due to limitations in empirical forcefield themselves [8,9,[26][27][28][29]. QM calculations are a more accurate alternative to study chemical phenomenon in proteins including aspects of protein-ligand interactions [15,[30][31][32][33][34][35] under investigation here, as well as their better known role in assessing chemical reactivity [36]. QM methods are typically employed on a small representation of the active site, consisting of the key residues for computational efficiency, which means the effects of potentially important longer range interactions will be lacking.…”

Adsorption of N/S heterocycles in the flexible metal–organic framework MIL-53(FeIII) studied by in situ energy dispersive X-ray diffraction

“…6. 43 Therefore it should interact more strongly with the framework m-(OH) groups along the backbone of MIL-53(Fe), explaining why it displaces isopropanol more easily. In doing this we have assumed that the decreasing peak area of the starting phase is inversely related to the growth of the fully open phase, i.e., we assume that the initial phase is replaced directly by the open phase, as indicated by the contour graphs.…”

In Silico Investigation of the Thyroid Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers

“…These descriptors were originally introduced by Klamt 32,33 and were successfully applied to the estimation of the hydrogen bonding strength, 34,35 a process observed between the hydroxyl groups of HO-PBDEs and the amino acid residues of TRβ, acting as a characteristic interaction for the thyroid hormone activity of HO-PBDE molecules. 20,30 In addition, these parameters have also been shown capable of addressing the electrostatic interactions, 34,35 another important molecular interaction that governs the activity of HO-PBDEs to TRβ. 20,30 Consequently, the local molecular descriptors are expected to be capable of quantifying the electronic interactions between HO-PBDEs and TRβ and to explain the activity mechanism because of their explicit physicochemical meanings.…”