Computational Chemistry Study Research Articles

Study of molecular interactions between Chitosan and Vi Antigen

Chitosan has attracted much interest due to its special physical and chemical properties related to drug administration. Nanoparticles delivery systems from Vi Antigen are a promising approach in the struggle against typhoid fever. In this paper, we reported the obtainment and the characterization of Vi Antigen by Infrared spectroscopy as well as Molecular Modeling and Computational Chemistry studies of the Chitosan-Vi Antigen interaction through theoretical models. The results of the theoretical and experimental Infrared spectroscopy showed important bands related to N-Acetyl and O-Acetyl groups present in Vi Antigen. Important interactions related to its adsorption were observed through three-dimensional optimized structures. Two models were proposed for the Chitosan-Vi Antigen in adsorption system, one as a monomer and another as an optimized tetrasaccharide antigen. The Molecular Modeling studies presented the best conformation and binding site on the nanoparticle Chitosan-Vi Antigen in models proposed. Interactions were observed between O-Acetyl and N-Acetyl groups the Vi Antigen and hydroxy, amino and methyl groups the Chitosan.

Proton Probability Distribution in the O···H···O Low-Barrier Hydrogen Bond: A Combined Solid-State NMR and Quantum Chemical Computational Study of Dibenzoylmethane and Curcumin.

We report a combined solid-state (1H, 2H, 13C, 17O) NMR and plane-wave density functional theory (DFT) computational study of the O···H···O low-barrier hydrogen bonds (LBHBs) in two 1,3-diketone compounds: dibenzoylmethane (1) and curcumin (2). In the solid state, both 1 and 2 exist in the cis-keto-enol tautomeric form, each exhibiting an intramolecular LBHB with a short O···O distance (2.435 Å in 1 and 2.455 Å in 2). Whereas numerous experimental (structural and spectroscopic) and computational studies have been reported for the enol isomers of 1,3-diketones, a unified picture about the proton location within an LBHB is still lacking. This work reports for the first time the solid-state 17O NMR data for the O···H···O LBHBs in 1,3-diketones. The central conclusion of this work is that detailed information about the probability density distribution of the proton (nuclear zero-point motion) across an LBHB can be obtained from a combination of solid-state NMR and plane-wave DFT computations (both NMR parameter calculations and ab initio molecular dynamics simulations). We propose that the precise proton probability distribution across an LBHB should provide a common basis on which different and sometimes seemingly contradicting experimental results obtained from complementary techniques, such as X-ray diffraction, neutron diffraction, and solid-state NMR, can be reconciled.

Nano Drug Deliverer for Ampicillin, Clavulanic Acid, Imipenem, Penicillin G and Ticarcillin

Ampicillin, Clavulanic acid, Imipenem, Penicillin G and Ticarcillin properties for the drug delivery with binding to SWCNNTs and SWBNNTs have been studied. Penicillin and its alteration Penicillin G or phenoxyacetic acid for Penicillin V is used for large scale production. Penicillin and other cell wall inhibitors are primarily specific against Gram positive bacteria because of higher percentage of peptidoglycan in the cell walls of these organisms. Ampicillin belonging to the penicillin group of beta lactam antibiotics, ampicillin is able to penetrate Gram positive and some Gram-negative bacteria. Imipenem (Primaxin) is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in 1980. It was the first member of the carbapenem class of antibiotics. Based on our previous works we have modeled and simulated a drug delivery system of those antibiotics. The investigation of those antibiotics in binding with single-walled carbon nanotube (SWCNT) and SWBNNTs have been studied by theoretical methods. It has been established the best structural and functional of those antibiotics. A number of computational chemistry studies carried out to understand the conformational preferences that may be attributed to stereo electronic effects. These results show the minimized structure of mentioned antibiotics with SWCNTs and SWBNNTs, calculated potential energy for important dihedral angles, and the effect of temperature on geometry of optimized structure. NMR by GIAO approximation, have been applied for determination of the situation in antibiotics-SWCNT and shifting. This model provides an atomistic analysis of the antibiotics-SWCNT strategy and its implications for further investigations of drugs.

A Flow Cytometric and Computational Approaches to Carbapenems Affinity to the Different Types of Carbapenemases.

The synergy of carbapenem combinations regarding Enterobacteriaceae producing different types of carbapenemases was study through different approaches: flow cytometry and computational analysis. Ten well characterized Enterobacteriaceae (KPC, verona integron-encoded metallo-β-lactamases –VIM and OXA-48-like enzymes) were selected for the study. The cells were incubated with a combination of ertapenem with imipenem, meropenem, or doripenem and killing kinetic curves performed with and without reinforcements of the drugs. A cephalosporin was also used in combination with ertapenem. A flow cytometric assay with DiBAC4-(3), a membrane potential dye, was developed in order to evaluate the cellular lesion after 2 h incubation. A chemical computational study was performed to understand the affinity of the different drugs to the different types of enzymes. Flow cytometric analysis and time-kill assays showed a synergic effect against KPC and OXA-48 producing-bacteria with all combinations; only ertapenem with imipenem was synergic against VIM producing-bacteria. A bactericidal effect was observed in OXA-48-like enzymes. Ceftazidime plus ertapenem was synergic against ESBL-negative KPC producing-bacteria. Ertapenem had the highest affinity for those enzymes according to chemical computational study. The synergic effect between ertapenem and others carbapenems against different carbapenemase-producing bacteria, representing a therapeutic choice, was described for the first time. Easier and faster laboratorial methods for carbapenemase characterization are urgently needed. The design of an ertapenem derivative with similar affinity to carbapenemases but exhibiting more stable bonds was demonstrated as highly desirable.

Macrocycles for the complexation of radiocesium: a concise review of crystallographic and computational studies

We review the crystallographic studies concerned with the complexes between cesium and different types of macrocycles. A detailed examination of the molecular structures indicates that the formation of several cesium–oxygen bonds is necessary in order for the macrocyle to capture a single Cs+ ion. In some cases, additional interactions such as cesium–arene and cesium–fluorine interactions may operate either alone or in combination with the above chemical bonds. Computational quantum chemistry studies based on experimental crystal structures represent a useful aid for elucidating the mechanism of binding and the role that explicit water molecules have in establishing ion–dipole interactions or H-bonds with the Cs+-macrocycle complex.

Preparation of Fe3O4-chitosan hybrid nano-particles used for humic acid adsorption

The adsorbent of Fe3O4-chitosan hybrid nano-particles have been prepared. In this process, these materials were initially synthesized by chemical co-precipitation and then cross-linked with chitosan to coat on the surface of Fe3O4 nano-particles. The characterization of the synthesized Fe3O4-chitosan hybrid nano-particles was performed using FTIR, XRD, TEM, EDX, BET and TGA. Finally, the Fe3O4-chitosan hybrid nano-particles were used for the adsorption of humic acid (HA) from aqueous solutions using batch adsorption technique. The influences of contact time, pH, adsorbent dosages, initial concentration of HA and temperatures on the adsorption process were studied. The adsorption isotherms were better fitted by Langmuir isotherm with the adsorption capacity was found to be 44.84mg/g. The results of the kinetic study showed that the adsorption of HA onto Fe3O4-chitosan hybrid nano-particles could be described by the pseudo second order kinetic model with a rate constant in the range of 0.032–0.104gmg−1min−1, respectively. Thermodynamic parameters data indicated that the HA adsorption process was non spontaneous and endothermic under the experimental conditions, with the values of Gibbs free energy (ΔGo) were in the range of 2.92–4.65kJ/mol; as well as the values of enthalpy (ΔHo), entropy (ΔSo) and the activation energy (Ea) were found to be 21.80kJ/mol, 57.55J/mol and 19.27kJ/mol, respectively. The computational chemistry study showed that the interaction between adsorbent and HA was occurred through the interaction between amine groups of chitosan and phenol groups of HA. The adsorption of HA from real sample using the prepared adsorbents showed that the Fe3O4-chitosan hybrid nano-particles has higher adsorption percentages than both Fe3O4 nano-particles and pure chitosan.

Crystal Structure Studies and Bronchodilation Properties of Novel Benzocycloheptapyridines

Benzocycloheptapyridines 6a and 6b were characterized by single crystal X-ray diffraction. Molecular packing exhibits that, molecules of compound 6a are linked in chains by one hydrogen bond of C–H···N type and set of H–π, and Cl–π interactions. However, compound 6b is stabilized by only Cl–π interactions. The main conformational difference between the experimental and theoretical optimized structures (using AM1, PM3 and DFT) was found in the relative orientation of the dichlorophenyl ring attached to the benzocycloheptapyridine system, which is attributed to the effect of the bulky chloride atom that prevents free rotation around the sigma bond attaching this ring with the heterocyclic system. Also, the lattice form plays an important role affecting the observed conformation. A similar behavior is also exhibited for the methyl group of the ethoxy function of 6b. The synthesized 6a reveals bronchodilation potency greater than that of the standard reference used, theophylline. Benzocycloheptapyridines were characterized by single crystal X-ray diffraction. Computational chemistry studies (AM1, PM3 and DFT) support the molecular structures. The synthesized analogues reveal promising bronchodilation properties.

Analysis of the CO2 absorption through a series of amines within the integration of a computational chemistry and process simulation scheme

In this study, the absorption of CO2 through primary and secondary amines is assessed employing two complementary approaches. The first one is a computational chemistry study on the thermodynamics of the reaction where the gas phase and the solvation effect are considered, as well as changes in temperature at 298.15K and 313.15K. The second one is the simulation of the absorption process in a packed column employing the rate-based approach, and using the kinetic and thermodynamic information provided by the computational chemistry study. The same operating conditions were kept in all studied systems; both studies, computational chemistry and process simulation, were found to be a good combination for this particular CO2 absorption problem, especially when there is a lack of kinetic data.

Crystal structure, spectroscopic investigations and quantum chemical computational study of 5-(diethylamino)-2-((3-nitrophenylimino)methyl)phenol

The Schiff base compound, 5-(diethylamino)-2-((3-nitrophenylimino)methyl)phenol, C17H19O3N3, was synthesized and characterized by IR, UV–Vis and single-crystal X-ray diffraction (XRD) technique. The title compound prefers enol tautomeric form in solid state as to X-ray, IR and UV–Vis spectra results. Also, using the TD-DFT method, the electronic absorption spectra of the title compound was computed in both the gas phase and ethanol solvent. The calculated results support that the enol form is more stable than keto form. The molecular geometry from the X-ray single-crystal determination of the title compound in the ground state was compared at the B3LYP and B3PW91 levels of the density functional method (DFT) with the 6-311 + G(d,p) basis set. The harmonic vibrational frequencies of the title compound were calculated using the B3LYP and B3PW91 methods with the 6-311G+(d,p) basis set. The calculated results were compared with the experimental determination results of the compound. The potential energy surface scans about important torsion angels were performed by B3LYP/6-311 + G(d,p) level of theory for the title compound. The energetic behaviors of the title compound in the solvent media were also examined using the B3LYP and B3PW91 methods with the 6-311 + G(d,p) basis set applying the Onsager and the polarizable continuum model (PCM). Besides, the molecular electrostatic potential map (MEP), frontier molecular orbitals (FMO) analysis and thermodynamic properties for the title compound were obtained with the same levels of theory. The nonlinear optical properties (NLO) of the title compound were performed in the solvent media using the B3LYP and B3PW91 methods with the 6-311 + G(d,p) level using the PCM model.

Stability and Characteristics of the Halogen Bonding Interaction in an Anion-Anion Complex: A Computational Chemistry Study.

Halogen bonding is the noncovalent interaction between the positively charged σ-hole of organohalogens and nucleophiles. In reality, both the organohalogen and nucleophile could be deprotonated to form anions, which may lead to the vanishing of the σ-hole and possible repulsion between the two anions. However, our database survey in this study revealed that there are halogen bonding-like interactions between two anions. Quantum mechanics calculations with small model complexes composed of halobenzoates and propiolate indicated that the anion-anion halogen bonding is unstable in vacuum but attractive in solvents. Impressively, the QM optimized halogen bonding distance between the two anions is shorter than that in a neutral system, indicating a possibly stronger halogen bonding interaction, which is verified by the calculated binding energies. Furthermore, natural bond orbital and quantum theory of atoms in molecule analyses also suggested stronger anion-anion halogen bonding than that of the neutral one. Energy decomposition by symmetry adapted perturbation theory revealed that the strong binding might be attributed to large induction energy. The calculations on 4 protein-ligand complexes from PDB by the QM/MM method demonstrated that the anion-anion halogen bonding could contribute to the ligands' binding affinity up to ∼3 kcal/mol. Therefore, anion-anion halogen bonding is stable and applicable in reality.

CO<sub>2</sub>化学吸収法に対する計算化学研究：エネルギー・環境問題への挑戦

アルカノールアミンによるCO2の化学吸収法は，発電所などの大規模CO2排出源における排出削減措置として現在最も有効な手段の1つと考えられている．現在，主にCO2回収過程におけるエネルギーコストの削減を目的として様々な吸収液が開発されており，CO2吸収液に用いられるアミンの分子設計が実験・理論の両面から精力的に進められている．本稿では，CO2とアミンの化学反応の理解・分析において理論計算，特に量子化学計算および第一原理分子動力学計算がどのように用いられてきたかを解説する．

The unique functional role of the C-HS hydrogen bond in the substrate specificity and enzyme catalysis of type 1 methionine aminopeptidase.

It is intriguing how nature attains recognition specificity between molecular interfaces where there is no apparent scope for classical hydrogen bonding or polar interactions. Methionine aminopeptidase (MetAP) is one such enzyme where this fascinating conundrum is at play. In this study, we demonstrate that a unique C-HS hydrogen bond exists between the enzyme methionine aminopeptidase (MetAP) and its N-terminal-methionine polypeptide substrate, which allows specific interaction between apparent apolar interfaces, imposing a strict substrate recognition specificity and efficient catalysis, a feature replicated in Type I MetAPs across all kingdoms of life. We evidence this evolutionarily conserved C-HS hydrogen bond through enzyme assays on wild-type and mutant MetAP proteins from Mycobacterium tuberculosis that show a drastic difference in catalytic efficiency. The X-ray crystallographic structure of the methionine bound protein revealed a conserved water bridge and short contacts involving the Met side-chain, a feature also observed in MetAPs from other organisms. Thermal shift assays showed a remarkable 3.3 °C increase in melting temperature for methionine bound protein compared to its norleucine homolog, where C-HS interaction is absent. The presence of C-HS hydrogen bonding was also corroborated by nuclear magnetic resonance spectroscopy through a change in chemical shift. Computational chemistry studies revealed the unique role of the electrostatic environment in facilitating the C-HS interaction. The significance of this atypical hydrogen bond is underscored by the fact that the function of MetAP is essential for any living cell.

Abstract LB-080: Reactivating RBL2/p130 oncosuppressive function as a new, possible antitumoral strategy

Abstract Deregulation of cell cycle control is the leading cause of cancer. The retinoblastoma (Rb) family members, including RB1/p105, RBL1/p107 and RBL2/p130, are crucial to restrain cell cycle progression and their inactivation, either direct or indirect, is a hallmark of most human tumors. In particular, RBL2/p130 emerging role in senescence and apoptosis, seems to contribute importantly to its tumor suppressor function. Furthermore, many studies largely contributed to establish RBL2/p130 as an important cancer target, which is inactivated by cell cycle kinases and whose deregulation underlies various cancer types. In this regard, we set out to restore RBL2/p130 function in tumors and exploit its tumor suppressive potential for cancer therapy. In particular, we have identified, through computational chemistry and molecular modeling studies, a small molecule able to act as a specific inhibitor of the CDK2-CycA complex and to reactivate the tumor suppressive function of RBL2/p130 in cancer. We analyzed by MTS assay the cytotoxic effect of our compound on a panel of different tumor cell lines and determined its IC50 values. We evaluated its effects on cell cycle and apoptosis by FACS and dissected its molecular mechanism of action by Western blot and RT-PCR. We found that our compound effectively inhibited proliferation of lung cancer and mesothelioma cell lines by specifically inhibiting CDK2-CycA activity towards RBL2/p130. The decrease in RBL2/p130 phosphorylation led to stabilization of its complex with the E2F4 transcriptional factor and consequent repression of their targets necessary for cell cycle progression, including CDK2 itself. Consistently, our compound arrested cell cycle and triggered apoptosis. Interestingly, apoptosis seemed to be mediated by RBL2/p130 itself because it was repressed in RBL2/p130-silenced cells. Furthermore, our compound proved to be active in an A549 xenograft model of lung cancer. Overall our findings indicate that the pharmacological reactivation of RBL2/p130 induces its cell-cycle restraining and pro-apoptotic functions, the latter being still largely unexplored, and identify a new possible therapeutic strategy for cancer treatment. Citation Format: Francesca Pentimalli, Luca Esposito, Iris Maria Forte, Carmelina Antonella Iannuzzi, Flavio Rizzolio, Tiziano Tuccinardi, Paola Indovina, Silvia Boffo, Antonio Giordano. Reactivating RBL2/p130 oncosuppressive function as a new, possible antitumoral strategy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-080. doi:10.1158/1538-7445.AM2015-LB-080

Computational chemistry insights in the REDOX Behaviour of Cr and W Fischer carbene complexes

An electrochemical study of a series of Fischer carbene complexes containing a hetero-aryl group showed that Cr and W carbenes exhibit different electrochemical behaviour. The Cr carbenes are oxidized in two one electron oxidation processes, namely Cr(0) to Cr(I) and Cr(I) to Cr(II). On the contrary, Fischer carbene complexes of tungsten are directly oxidized from W(0) to W(II). The first reduction process observed for both W- and Cr- carbenes, is a one electron process. A density functional theory (DFT) computational chemistry study of the electronic structure of the Cr- and W-carbenes, showed that the oxidation is metal based and the reduction is located on the carbene ligand. The DFT calculations further showed that the Cr(II) species is a triplet and the W(II) species a closed shell singlet. The DFT calculated energies of the HOMO and LUMO of the neutral carbenes relate linearly to the experimental oxidation and reduction potential, respectively. These mathematical relationships obtained can be used to predict experimentally measured potentials of related Fischer carbene complexes.

Computational Chemistry and Electrochemical Studies of Adsorption Behavior of Organic Additives during Gold Deposition in Cyanide-free Electrolytes

In this work, a combined approach using density functional theory (DFT), molecular dynamic simulations, and electrochemical experiments was developed to study organic additives used for a cyanide-free gold electrodeposition process. When 5,5-dimethylhydantoin (DMH) is used as the complexing agent, organic additives with either imino groups or nitrogenous heterocyclic rings including polyethyleneimine (PEI), 2,2′-bipyridine, and nicotinic acid (NA) were systematically investigated. Electronic properties and orbital information of these studied additives were determined by quantum chemical calculations based on DFT. Compared to the other additives, PEI was predicted as the most promising one for the introduced DMH based gold electrodeposition. The theoretical prediction was further verified by using experimental results. In particular, the cathodic polarization of the gold electrodeposition was significantly improved in the presence of PEI. Also, the resulting gold electrodeposit shows obviously finer crystalline particles largely. In addition, molecular dynamic simulations determined that PEI molecules possess optimized adsorption behavior on the gold surface, suggesting its effectiveness to be additive in the studied cyanide-free Au-electrodeposition electrolytes.

Quantum chemical study on influence of the substitution effect on the structural and electronic properties and intramolecular hydrogen bonding of 2-nitrophenyl hydrosulfide in ground and electronic excited state

A density functional theory (DFT)-based quantum chemical computational study has been carried out to characterize the intramolecular hydrogen bonding (IMHB) interaction in 2-nitrophenyl hydrosulfide. This compound and its 24 derivatives are optimized by B3LYP method using 6-311++G** basis set in the gas phase and the water solution. The following substituents have been taken into consideration: F, Cl, Br, C2H5, CH3, CF3, NHCOCH3, NO2, OH, OCH3, SH, CH2F, CH2Cl, CH2Br, CH2OH, SH, SCH3, SCF3, SCOCH3, CH2CF3, CH2OCH3, CHO, COCH3, and OCHF2. The IMHB interaction has been explored by calculation of electron density ρ(r) and Laplacian ∇2ρ(r) at the bond critical point using atoms-in-molecule (AIM) theory. The electron density (ρ) and Laplacian (∇2ρ) properties, estimated by AIM calculations, indicate that H6···O1 bond possesses low ρ and positive ∇2ρ values which are in agreement with electrostatic character of the HBs, whereas S5–H6 bond has covalent character (∇2ρ < 0). The natural bond orbital analysis is applied to get a more precise insight into the nature of such H6···O1 interactions. Vibrational frequencies, several well-established indices of aromaticity, and physical properties such as dipole moment, chemical potential, and chemical hardness of these compounds have been systematically explored. Also, the excited-state properties of intramolecular hydrogen bonding in these systems have been investigated theoretically using the time-dependent DFT method.

Collision-Induced Dissociation Analysis of Brevianamide A and C in Electrospray Ionization Mass Spectrometry

Brevianamides A and C are isomeric cyclic peptides with several reported biological activities, isolated from diverse microorganisms. Currently, there has been no previous investigation of brevianamide fragmentation utilizing electrospray ionization mass spectrometry (ESI-MS). In this work experiments were carried out in the positive mode using two different spectrometers (low and high resolution) with an ESI source. Computational chemistry studies helped identify the protonation sites based upon atomic charges, proton affinities and molecular orbitals, computed using the B3LYP/6-31++G (d,p) model. The data suggests that the presence of the allylic position of the lactamic N in brevianamides C governs its fragmentation pathways. Distinguishing between brevianamides A and C using positive ion electrospray tandem mass spectrometry (ESI(+)MS/MS) is made possible by the spectral difference of each isomer and offers an alternative to other spectroscopic techniques.

Catalytic performance of different carbon materials for hydrogen production in sulfur–iodine thermochemical cycle

This study examines four carbon materials through a series of characterization methods and a hydrogen iodide (HI) decomposition test. Applying a traditional structure to carbon materials facilitates the quantitative analysis of the four samples. The X-ray diffraction and Raman spectroscopy results indicate that lesser stacked graphite-like layers and shorter lateral diameter La result in higher disordering structure. However, the quantity of active sites is not determined only by the degree of disordering. The aliphatic carbon in the inter-layer correlations decreases the amount of graphite carbon and occupies its edge, thereby inhibiting the formation of edge sites in carbon materials. A low ratio of amorphous carbon with a high degree of disordering corresponds to a high concentration of surface active sites associated with the edges of graphite-like layers. The catalytic performance combined with characterization results demonstrates that the edges of graphite carbon are active sites in HI decomposition. A computational chemistry study is also conducted to illustrate the dominant role of edge sites in the reaction. The calculation results build a detailed mechanism of the catalytic decomposition of HI over the carbon materials and verify that the adsorbed I on the edge sites facilitate the HI decomposition.

Unstable, metastable, or stable halogen bonding interaction involving negatively charged donors? A statistical and computational chemistry study.

The noncovalent halogen bonding could be attributed to the attraction between the positively charged σ-hole and a nucleophile. Quantum mechanics (QM) calculation indicated that the negatively charged organohalogens have no positively charged σ-hole on their molecular surface, leading to a postulation of repulsion between negatively charged organohalogens and nucleophiles in vacuum. However, PDB survey revealed that 24% of the ligands with halogen bonding geometry could be negatively charged. Moreover, 36% of ionizable drugs in CMC (Comprehensive Medicinal Chemistry) are possibly negatively charged at pH 7.0. QM energy scan showed that the negatively charged halogen bonding is probably metastable in vacuum. However, the QM calculated bonding energy turned negative in various solvents, suggesting that halogen bonding with negatively charged donors should be stable in reality. Indeed, QM/MM calculation on three crystal structures with negatively charged ligands revealed that the negatively charged halogen bonding was stable. Hence, we concluded that halogen bonding with negatively charged donors is unstable or metastable in vacuum but stable in protein environment, and possesses similar geometric and energetic characteristics as conventional halogen bonding. Therefore, negatively charged organohalogens are still effective halogen bonding donors for medicinal chemistry and other applications.

The receptor concept in 3D: from hypothesis and metaphor to GPCR-ligand structures.

The first mentioning of the word "receptor" for the structure with which a bioactive compound should react for obtaining its specific influence on a physiological system goes back to the years around 1900. The receptor concept was adapted from the lock and key theory for the enzyme substrate and blockers interactions. Through the years the concept, in the beginning rather being a metaphor, not a model, was refined and became reality in recent years. Not only the structures of receptors were elucidated, also the receptor machineries were unraveled. Following a brief historical review we will describe how the recent breakthroughs in the experimental determination of G protein-coupled receptor (GPCR) crystal structures can be complemented by computational modeling, medicinal chemistry, biochemical, and molecular pharmacological studies to obtain new insights into the molecular determinants of GPCR-ligand binding and activation. We will furthermore discuss how this information can be used for structure-based discovery of novel GPCR ligands that bind specific (allosteric) binding sites with desired effects on GPCR functional activity.