H-bond Donor Sites Research Articles

Molecular Dynamics Study of Hydrogen Bond Structure and Tensile Strength for Hydrated Amorphous Cellulose.

Molecular dynamics (MD) simulations were conducted to investigate the hydrogen-bond (H-bond) structure and its impact on the tensile strength of hydrated amorphous cellulose. The study identifies a stable intramolecular H-bond between the hydroxyl group at position 3 and the ether oxygen at position 5 (OH3···O5). Intermolecularly, the hydroxyl groups at positions 2 (OH2) and 6 (OH6) form stable H-bonds. Young's modulus, maximum tensile strength, and corresponding strain were calculated as functions of moisture content, while the H-bond network, water cluster formation, and cellulose chain orientation during tensile simulations were analyzed to elucidate mechanical properties. The substitution effect of cellulose on Young's modulus is also examined, revealing that the substitution of OH3 for a hydrophobic group minimally affects Young's modulus, but substitutions at OH2 and OH6 significantly reduce tensile strength due to their roles as key intermolecular H-bond donor sites.

End-capping of hydrogen bonds: A strategy for blocking the proton conduction pathway in aqueous electrolytes

Sustainable battery development is becoming a key goal for storing renewable energy on a large scale. Toward this goal, great hopes are placed on the use of aqueous electrolytes. However, with high expectations, come increasing challenges, represented by the parasitic hydrogen evolution reaction (HER) on the anode of aqueous batteries. Here, we propose a new strategy to mitigate HER in aqueous batteries by the regulation of mass transfer kinetics, namely blocking the pathway of proton conduction by the end-capping of H-bond using N-methyl-2-pyrrolidone (NMP). The NMP structure possesses the H-bond acceptor but no H-bond donor sites, a feature that can effectively cut off H-bond propagation, and further block the pathway of proton transport in aqueous electrolytes. Hence, the modulated electrolyte confers a combination of enhanced cathodic and anodic stability, dendrite-free metal plating/stripping, and a high average Coulombic efficiency (CE) of 99.2%. Further, the end-capping of the H-bond network in electrolytes results in substantially more stable full-cell batteries that pair the metal anode with Prussian blue analogue (PBA) and polyaniline (PANI) cathodes at both room and low temperature. The “end-capping” concept in polymers is broadened to aqueous solutions for the first time here, providing a potential direction to revolutionize aqueous batteries for efficient energy storage.

Cryptic solvation dynamics of potential antineoplastic Azapodophyllotoxin: Short and long range charge transfer and distinct H-bonding motifs demystify its swinging emissive behaviour

Azapodophyllotoxin, the nitrogen analogue of antitumor podophyllotoxin, are new series of fascinating aspirants of anticancer drugs. The potential bioactive azapodophyllotoxin 5-(2-Hydroxyethyl)-9-(3,4,5-trimethoxyphenyl)-6,9-dihydro-[1,3]dioxolo[4,5–g]furo[3,4–b]quinolin-8(5H)-one (HTDQ) has been found to be highly effective against various cancer cell lines as compared to its minimal toxicity against normal cell lines. With an ulterior motive of exploring fluorescence properties of this promising antineoplastic candidate in biological environment, the intricate details of its ground and excited state solvation and solvation dynamics are investigated using steady state and Time resolved spectroscopic techniques. The experimental observations are substantiated by DFT and TD-DFT based quantum chemical calculations along with in silico molecular dynamics simulation. The solvatochromic behaviour of HTDQ reveals its sensitivity towards solvent polarity and proticity. The charge delocalization within HTDQ framework in ground state (G.S) entirely differs from that of in excited state (E.S). The change in polarity of the medium induces a peculiar short range intramolecular charge delocalization in G.S itself, forming a zwitterionic structure and endorses the unusual absorption characteristics. Whereas, in the E.S, it undergoes a long range intramolecular charge transfer (ICT). In non-polar solvents, the long range ICT induces stacking interaction between two dipolar HTDQ molecules leading to the formation of a new short-lived less emissive excimer species. However, in aprotic and protic polar solvents, the scenario is individually different due to the presence of H-bond donor (hydroxyl hydrogen atom) as well as acceptor sites (oxygen atoms) in the molecular framework of HTDQ. In aprotic solvents, the formation of H-bonds occurs due to presence of hydrogen acceptor site in the solvent that boost up the emission intensity to its maxima. In polar protic solvents, HDTQ subsumes both of its H-bond donor and acceptor sites and further strengthens the H-bonding interactions, which essentially stabilizes the probe molecule within the solvent shell and open up the non-radiative decay channels thereby reducing the emission intensity. HTDQ exhibits bathochromic shift in the emission spectra with increasing solvent polarity, with some exceptional shifts in 1,4 dioxane and THF, which may stem from another interesting conformational polarization of non-polar chair form to polar boat form of the solvent itself. Thus, the different spectroscopic aspects dealt herein demystify the impact of solvent milieu on the solute–solvent interactions and the interesting emissive nature of this potential therapeutic HTDQ that may provide impetus to develop new class of theragnostic agent with promising imaging capability and improved anti-neoplastic activities.

Properties of Hydrogen-Bonded Networks in Ethanol-Water Liquid Mixtures as a Function of Temperature: Diffraction Experiments and Computer Simulations.

New X-ray and neutron diffraction experiments have been performed on ethanol–water mixtures as a function of decreasing temperature, so that such diffraction data are now available over the entire composition range. Extensive molecular dynamics simulations show that the all-atom interatomic potentials applied are adequate for gaining insight into the hydrogen-bonded network structure, as well as into its changes on cooling. Various tools have been exploited for revealing details concerning hydrogen bonding, as a function of decreasing temperature and ethanol concentration, like determining the H-bond acceptor and donor sites, calculating the cluster-size distributions and cluster topologies, and computing the Laplace spectra and fractal dimensions of the networks. It is found that 5-membered hydrogen-bonded cycles are dominant up to an ethanol mole fraction xeth = 0.7 at room temperature, above which the concentrated ring structures nearly disappear. Percolation has been given special attention, so that it could be shown that at low temperatures, close to the freezing point, even the mixture with 90% ethanol (xeth = 0.9) possesses a three-dimensional (3D) percolating network. Moreover, the water subnetwork also percolates even at room temperature, with a percolation transition occurring around xeth = 0.5.

New insights about the serine/threonine protein kinase substrates from Mycobacterium tuberculosis using molecular docking, quantum similarity analysis and DFT calculations

Background: The protein kinases present in the human body have received a lot of attention because of the interest in their use as therapeutic targets. However, little is known about the protein kinases associated with tuberculosis. For these reasons, this research investigates a new point of view regarding the crystallized serine/threonine protein kinases Pkn A, B and G of Mycobacterium tuberculosis. Methods: The conformational analysis shows a DFG-in motif in Pkn B and G and a DFG-out motif in Pkn A. For all the protein kinases that have been studied, the gatekeeper residue is methionine. A study of the protein kinases with their ligands was also conducted to find new insights on the binding site with a series of ligands associated to protein kinases Pkn A, B and G through molecular docking. The residues with hydrogen bonds on the hinge zone of Pkn A are GLU96 and VAL 98, of Pkn B are GLU 93 and VAL 95 and of Pkn G are GLU233 and VAL235. Results: The results show the H-bond acceptor and H-bond donor sites on the hinge zone to all ligands, establishing a structural model of the ligands on the active site with two or three interactions in this zone. This interaction model was validated using density functional theory calculations (by means of net charges and images of the electrostatic potential) and molecular quantum similarity analysis, showing a high correlation between the electronic and steric effects in each ATP complex studied. Conclusions: In this work we can see that the interactions of the hinge zone are characterized by the key factor of one or two H-bonds acceptors and one H-bond donor in the ligands of this zone. The quantum similarity analysis shows good correlation between the steric and electronic effects in each ATP complex.

Molecular tectonics: Self-assembly of pyridyl bearing nucleobases

A library of organic tectons (1–3 and 5) combining nucleobases and a pyridyl moiety connected at the position 4 of the ring was designed and synthesized. The solid-state structure of tectons 1–3 was investigated by X-ray diffraction on single crystal. Owing to the self-complementary nature of the tectons bearing both H-bond donor and acceptor sites, compounds 1–3 self-assemble into H-bonded networks. The dimension of the latter is further increased when taking into account π-π stacking interactions.

Tripodal tris(diamide) receptor having H-bond donors and acceptors on trindane platform for H2PO4− recognition

A new C3v-symmetric tris(diamide) receptor 2 possessing both H-bond donor and acceptor sites was synthesized and characterized by various spectral data. The anion recognition ability of receptor 2 was investigated by 1H NMR in DMSO-d6. Among the tested anions (F−, Cl−, Br−, I−, NO3−, HSO4− and H2PO4−), the receptor 2 shows high selectivity towards H2PO4− anion. The amide-NH protons peaks of receptor 2 at δ 10.42 and δ 8.23 ppm were broadened and shifted to downfield region in the presence of H2PO4−. The appended arms with tris(diamide) H-bond donors and pyridine H-bond acceptors of receptor 2 provide a preorganized cavity to encapsulate the H2PO4− through multiple hydrogen bonds. The 1H NMR titration measures the binding constant (Ka) of 293 M−1 for the host–guest complex formed between receptor 2 and H2PO4−. Further, the possible 3D structure of receptor 2 and its complex with H2PO4− anion was proposed through density functional theory method.

Removal of 2,4-D, glyphosate, trifluralin, and butachlor herbicides from water by polysulfone membranes mixed by graphene oxide/TiO2 nanocomposite: study of filtration and batch adsorption.

Degradation or decomposition of the chemical herbicides by natural reagents after using can lead to produce various types of harmful intermediates. Ultrafiltration by the mixed matrix membranes blended with the graphene oxide/TiO2 can remove the residual herbicides from aqueous solution. Graphene oxide/TiO2x% (x = 10, 30, 50%) was prepared by solvothermal method and blended by polysulfone to prepare GO/TiO2/PSf membranes for dynamic rejection of aqueous solutions of glyphosate, 2,4-D, butachlor, and trifluralin in a dead-end flow system. The blended membranes were also applied for the adsorption of herbicides in batch experiments. Addition of GO/TiO2 nanocomposite increased water flux from 7.3 for pure membrane to 211-326kg/m2h for mixed matrix samples in order to increase of the membrane porosity and surface hydrophilicity. The herbicides rejections were found in the range of 50-70% related to GO/TiO2 content. It was found that the membrane blended with 0.5wt.% of GO/TiO2(10%) demonstrated the most efficiency. Details of dynamic filtration showed that the blended membrane acted based on the size exclusion mechanism. Adsorption experiments indicated that the strong attractions between H-bond donor sites of the herbicide and GO/TiO2 nanoparticles in membranes played a key role in the increase of adsorption of herbicides on the membrane.

H-Bond Self-Assembly: Folding versus Duplex Formation.

Linear oligomers equipped with complementary H-bond donor (D) and acceptor (A) sites can interact via intermolecular H-bonds to form duplexes or fold via intramolecular H-bonds. These competing equilibria have been quantified using NMR titration and dilution experiments for seven systems featuring different recognition sites and backbones. For all seven architectures, duplex formation is observed for homo-sequence 2-mers (AA·DD) where there are no competing folding equilibria. The corresponding hetero-sequence AD 2-mers also form duplexes, but the observed self-association constants are strongly affected by folding equilibria in the monomeric states. When the backbone is flexible (five or more rotatable bonds separating the recognition sites), intramolecular H-bonding is favored, and the folded state is highly populated. For these systems, the stability of the AD·AD duplex is 1–2 orders of magnitude lower than that of the corresponding AA·DD duplex. However, for three architectures which have more rigid backbones (fewer than five rotatable bonds), intramolecular interactions are not observed, and folding does not compete with duplex formation. These systems are promising candidates for the development of longer, mixed-sequence synthetic information molecules that show sequence-selective duplex formation.

Bis(pyrrole-benzimidazole) conjugates as novel colorimetric sensor for anions

Novel bis(pyrrole-benzimidazole) (PYBI) conjugates were investigated as colorimetric anion recognition motif by employing multiple donor sites. In this regard, PYBI derivatives where pyrrole unit is connected to the C2 position of benzimidazole via its $$\alpha $$ -position were synthesized and their anion recognition behavior were evaluated by UV-Vis, fluorescence and $$^{1}\hbox {H NMR}$$ spectroscopy. PYBI selectively interacts with fluoride ion, whereas introduction of nitro group on the benzimidazole moiety enhances the binding affinity by at least one order, albeit at the expense of the selectivity. Bridging of two PYBIs led to interesting cooperative effect between the two subunits, which gets enhanced upon changing the spacer between the two from non-conjugating type $$({ sp}^{3}\hbox {-C})$$ to conjugating one (quinoxaline). This also affects the way they interact with anions, with the latter moiety displaying very interesting stepwise double deprotonation of benzimidazole protons upon addition of fluoride ions with strong colorimetric as well as fluorometric response. Further, acidity of the H-bond donor sites was found to play pivotal role in the anion complexation mechanism and selectivity. SYNOPSIS Novel bis(pyrrole-benzimidazole) (PYBI) conjugates where pyrrole units are connected to the C2 position of benzimidazole via its $$\alpha $$ -position were synthesized and their anion recognition behavior were evaluated. Anion selectivity and mode of interaction was found to depend on the nature of the substituent and the spacer between the two PYBI units.

The Limit of Intramolecular H-Bonding.

Hydrogen bonds are ubiquitous interactions in molecular recognition. The energetics of such processes are governed by the competing influences of pre-organization and flexibility that are often hard to predict. Here we have measured the strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable linker. A striking distance-dependent threshold was observed in the intramolecular interaction energies. H-bonds were worth less than -1 kJ mol-1 when the interacting groups were separated by ≥6 rotating bonds, but ranged between -5 and -9 kJ mol-1 for ≤5 rotors. Thus, only very strong external H-bond acceptors were able to compete with the stronger internal H-bonds. In addition, a constant energetic penalty per rotor of ∼5-6 kJ mol-1 was observed in less strained situations where the molecule contained ≥4 rotatable bonds.

Design and anti-HIV activity of arylsulphonamides as non-nucleoside reverse transcriptase inhibitors

Design and anti-HIV activity of a series of arylsulphonamide derivatives as possible non-nucleoside reverse transcriptase inhibitors have been discussed. Compounds designed on the basis of Lipinski’s rule of five and having H-bond donor and acceptor sites were synthesized and screened in vitro to assess their human immunodeficiency virus type 1 reverse transcriptase inhibitory activity using TZM-bl cells. In silico studies using Discovery Studio 3.0 software showed that these molecules formed H-bonds and exhibited π–π, π–+ interactions, with amino acids in the non-nucleoside inhibitor binding pocket, and formed more stable complexes (total interaction energy in the range of (−) 47.85–(−) 77.01 kcal/mol) with human immunodeficiency virus type 1 reverse transcriptase in comparison to nevirapine and etravirine, (−) 45.79 and (−) 61.43 kcal/mol, respectively, and thus, lower EC50 values were predicted. The molecule, 4-(4-chloro-benzenesulphonyl amino)-N-(1H-indazole-5-yl)-benzamide showed significant inhibition of human immunodeficiency virus type 1 growth under in vitro conditions with EC50 value in the range of 4.89 × 10−5 μm. However, its selectivity index value was 2.45 only, which was much lower than nevirapine and etravirine. The reverse transcriptase analysis, based on luciferase reporter assay, of this compound proved its nature as non-nucleoside reverse transcriptase inhibitors. Though the molecules showed low inhibitory action against human immunodeficiency virus type 1 under in vitro conditions, the idea to develop non-nucleoside reverse transcriptase inhibitors was vindicated.

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

Lattice interactions and aggregation in solution—can the two be related?

Comparison is made of the crystal structures of two different solvates of a molecule containing both H-bond donor and acceptor sites, which is found either as a monomer or a hexamer. The solid state features are analysed with respect to the behaviour seen in solutions in the same solvents as found in the crystal lattices. Dimethylsulfoxide appears to be particularly effective in preventing aggregation not only through H-bond acceptance but also through contacts at S which may block H-bond acceptor sites adjacent to donors.

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Growth suppression of many non-COX-2 expressing tumor cells can be exhibited by COX-2 inhibitors, where supplementation of cells with exogenous prostaglandins fails to rescue the cells from growth inhibition. It can, therefore, be speculated that anti-cancer properties of some COX-2 inhibitors may be contributed by the COX-2-independent effects also. Some of the derivatives obtained from certain COX-2 inhibitors which show non-COX-2 inhibitory mechanism have revealed some significant anti-cancer activities. From a COX-2 selective inhibitor nimesulide, an analog JCC76 is derived which is a non-COX-2 active compound and shows inhibition of SKBR-3 breast cancer cell growth. Other JCC76 derived inhibitors also played significant role in SKBR-3 cell inhibition. An analog-based study was done using pharmacophore modeling and 3D-QSAR to provide clues for potential lead compound designing. A five point pharmacophore ADHRR was generated using 39 JCC76-derived SKBR-3 inhibitors. The validated pharmacophore alignment was used for further 3D-QSAR analysis, which presented a good R 2 value of 0.562, 0.982, and 0.848 for atom-based QSAR, CoMFA, and CoMSIA model, respectively. All the QSAR models presented good statistical significance and predictivity. The corresponding Q 2 values for each model are 0.513, 0.649, and 0.518, respectively. Both the pharmacophore and CoMSIA results displayed that the H-bond donor and acceptor sites are the key structural feature for JCC76-derived non-COX-2-dependent inhibitors with high activity.

The Crystal Structure of Benzimidazole Complex with Chloranilic Acid Hydrate Adduct

Proton transfer realized through intermolecular H-bonds enables charge and energy transfer in biological systems, particularly in enzymes.1 Protonation of the donor from acidic acceptors are generally a route for the formation of ion pair adducts. Chloranilic acid (CLA) exhibits electron-acceptor properties on one hand and acidic properties leading to formation of H-bonds on the other hand, and usually utilized as a template for generating tightly bound self assemblies with various organic bases, and also as a model compound for investigating hydrogen transfer motions in O–H·N and N–H·O hydrogen bond systems.2 Benzimidazole (BIZ) is an organic base, and has H-bond donor site as well as acceptor site. The synthesis and spectroscopic studies, as well as crystallographic studies3,4 of charge transfer complexes formed between CLA and BIZ derivatives have been reported and the knowledge utilized in the field of drug-receptor binding mechanisms in medicinal chemistry. However, there is no report on BIZ complex with CLA, and is being pursued by our group. Our attempt to obtain such a complex resulted in the formation of BIZ with CLA hydrate adduct. As per our interest in studying proton transfer complexes, we found it prudent to report the role played by water in influencing proton transfer in the adduct, as well as contributing to increased number of H-bonds. The complex was obtained by dissolving a 1:1 mixture of BIZ (0.24 g, 2 mmol) and CLA (0.42 g, 2 mmol) in 20 ml methanol and allowed to evaporate slowly at room temperature. Suitable crystals were obtained after two weeks and characterized through X-ray diffraction at 150 K. Crystal data and details of data collection are given in Table 1. The structure solution was carried out with direct methods using the programs SIR 92 or superflip within the CRYSTALS software suite, and refined by full-matrix leastsquares methods based on F2. The chemical structure of BIZ/CLA·H2O adduct is shown in X-ray Structure Analysis Online

Relationship between Chemical Structure and Supramolecular Effective Molarity for Formation of Intramolecular H-Bonds

Effective molarity (EM) is a key parameter that determines the efficiency of a range of supramolecular phenomena from the folding of macromolecules to multivalent ligand binding. Coordination complexes formed between zinc porphyrins equipped H-bond donor sites and pyridine ligands equipped with H-bond acceptor sites have allowed systematic quantification of EM values for the formation of intramolecular H-bonds in 240 different systems. The results provide insights into the relationship of EM to supramolecular architecture, H-bond strength, and solvent. Previous studies on ligands equipped with phosphonate diester and ether H-bond acceptors were inconclusive, but the experiments described here on ligands equipped with phosphine oxide, amide, and ester H-bond acceptors resolve these ambiguities. Chemical double-mutant cycles were used to dissect the thermodynamic contributions of individual H-bond interactions to the overall stabilities of the complexes and hence determine the values of EM, which fall in the range 1-1000 mM. Solvent has little effect on EM, and the values measured in toluene and 1,1,2,2-tetrachloroethane are similar. For H-bond acceptors that have similar geometries but different H-bond strengths (amide and ester), the values of EM are very similar. For H-bond acceptors that have different geometries but similar H-bond strengths (amide and phosphonate diester), there is little correlation between the values of EM. These results imply that supramolecular EMs are independent of solvent and intrinsic H-bond strength but depend on supramolecular architecture and geometric complementarity.

Interplay of Self-Association and Solvation in Polar Liquids

The association constants for formation a 1:1 complex between 4-phenyl azophenol and tri-n-butylphosphine oxide were measured in mixtures of n-octane and n-decanol, n-octane and n-hexanoic acid, and n-octane and 2-ethylhexyl acetamide. The experiments provide insight into the competition between solvent self-association and solvent-solute interactions in these systems. The solvation properties of the three polar solvents are quite different from one another and from polar solvents that do not self-associate. Carboxylic acids form dimers in concentrated solution (>1 mM in alkanes). Carboxylic acid dimers have exposed H-bond acceptor sites that solvate H-bond donor solutes with a similar binding affinity to carboxylic acid monomers. The carboxylic acid H-bond donor site is inaccessible in the dimer and is not available to solvate H-bond acceptor solutes. The result is that solvation of H-bond acceptor solutes is in competition with solvent dimerization, whereas solvation of H-bond donor solutes is not. Secondary amides form linear polymers in concentrated solution (>10 mM in alkanes). The solvation properties of the secondary amide aggregates are similar to those of carboxylic acid dimers. Solvation of H-bond acceptor solutes must compete with solvent self-association, because the amide H-bond donor site is not accessible in the middle of a polymeric aggregate. However, the amide aggregates have exposed H-bond acceptor sites, which solvate H-bond donor solutes with similar binding affinity to amide monomers. Alcohols form cyclic tetramers at concentrations of 100 mM in alkanes, and these cyclic aggregates are in equilibrium with linear polymeric aggregates at concentrations above 1 M. The alcohol aggregates have exposed H-bond acceptor sites that solvate H-bond donor solutes with similar binding affinity to alcohol monomers. Although the alcohol H-bond donor sites are involved in H-bond interactions with other alcohols in the aggregates, these sites are sufficiently exposed to form a second bifurcated H-bond with H-bond acceptor solutes, and these interactions have a similar binding affinity to alcohol monomers. The result is that self-association of alcohols does not compete with solvation of solutes, and alcohols are significantly more polar solvents than expected based on the properties of alcohol monomers.

Pharmacophore modelling and electronic feature analysis of hydroxamic acid derivatives, the HIV integrase inhibitors

Hydroxamic acid derivatives with metal ion binding properties were collected from the literature to generate a pharmacophore and 3D-QSAR model for HIV strand transfer inhibition. The derived pharmacophore model (AAAHRR) recognizes both metal ion binding site and hydrophobic group. The QSAR model generated using this hypothesis expressed statistical significance (r 2 = 0.971 for the training set and q 2 = 0.913 for the test set). The ability of this pharmacophore model to retrieve other metal ion binding inhibitors was examined by screening the ChemBank database (ligandinfo) incorporated with 10 known strand transfer inhibitors. The studied favourable and unfavourable contours of chemical features (H-bond donor, acceptor and hydrophobic sites) revealed the role of hydrophobic substitution at the fluorobenzene ring and cyclization of the metal ion binding hydroxamic acid in effective integrase inhibition. Analysis of the frontier orbitals, HOMO and LUMO revealed that the nucleophilic / electrophilic interactions depend on the significant overlapping observed at the azaindole and hydroxamic acid groups. In essence, the generated pharmacophore model is competent enough to disclose the essential site-specific interactions involved in the inhibition of HIV integrase, and hence can be used in virtual screening to identify novel scaffolds as leads with increased anti-viral potency.

Footprinting molecular electrostatic potential surfaces for calculation of solvation energies

A liquid is composed of an ensemble of molecules that populate a large number of different states, so calculation of the solvation energy of a molecule in solution requires a method for summing the interactions with the environment over all of these states. The surface site interaction model for the properties of liquids at equilibrium (SSIMPLE) simplifies the surface of a molecule to a discrete number of specific interaction sites (SSIPs). The thermodynamic properties of these interaction sites can be characterised experimentally, for example, through measurement of association constants for the formation of simple complexes that feature a single H-bonding interaction. Correlation of experimentally determined solution phase H-bond parameters with gas phase ab initio calculations of maxima and minima on molecular electrostatic potential surfaces (MEPS) provides a method for converting gas phase calculations on isolated molecules to parameters that can be used to estimate solution phase interaction free energies. This approach has been generalised using a footprinting technique that converts an MEPS into a discrete set of SSIPs (each described by a polar interaction parameter, εi). These SSIPs represent the molecular recognition properties of the entire surface of the molecule. For example, water is described by four SSIPs, two H-bond donor sites and two H-bond acceptor sites. A liquid mixture is described as an ensemble of SSIPs that represent the components of the mixture at appropriate concentrations. Individual SSIPs are assumed to be independent, so speciation of SSIP contacts can be calculated based on properties of the individual SSIP interactions, which are given by the sum of a polar (εiεj) and a non-polar (E(vdW)) interaction term. Results are presented for calculation the free energies of transfer of a range of organic molecules from the pure liquid into water, from the pure liquid into n-hexadecane, from n-hexadecane into water, from n-octanol into water, and for the transfer of water from pure water into a range of organic liquids. The agreement with experiment is accurate to within 1.6-3.9 kJ mol(-1) root mean square difference, which suggests that the SSIMPLE approach is a promising method for estimation of solvation energies in more complex systems.