Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation

Molecular modeling and structure-activity relationship studies were performed to propose a model for binding of the neurotransmitter serotonin (5-HT) to the human serotonin transporter (hSERT). Homology models were constructed using the crystal structure of a bacterial homologue, the leucine transporter from Aquifex aeolicus, as the template and three slightly different sequence alignments. Induced fit docking of 5-HT into hSERT homology models resulted in two different binding modes. Both show a salt bridge between Asp98 and the charged primary amine of 5-HT, and both have the 5-HT C6 position of the indole ring pointing toward Ala173. The difference between the two orientations of 5-HT is an enantiofacial discrimination of the indole ring, resulting in the 5-hydroxyl group of 5-HT being vicinal to either Ser438/Thr439 or Ala169/Ile172/Ala173. To assess the binding experimentally, binding affinities for 5-HT and 17 analogues toward wild type and 13 single point mutants of hSERT were measured using an approach termed paired mutant-ligand analogue complementation (PaMLAC). The proposed ligand-protein interaction was systematically examined by disrupting it through site-directed mutagenesis and re-establishing another interaction via a ligand analogue matching the mutated residue, thereby minimizing the risk of identifying indirect effects. The interactions between Asp98 and the primary amine of 5-HT and the interaction between the C6-position of 5-HT and hSERT position 173 was confirmed using PaMLAC. The measured binding affinities of various mutants and 5-HT analogues allowed for a distinction between the two proposed binding modes of 5-HT and biochemically support the model for 5-HT binding in hSERT where the 5-hydroxyl group is in close proximity to Thr439.     

Computational Simulations Highlight the IL2Rα Binding Potential of Polyphenol Stilbenes from Fenugreek

Widely used in global households, fenugreek is well known for its culinary and medicinal uses. The various reported medicinal properties of fenugreek are by virtue of the different natural phytochemicals present in it. Regarded as a promising target, interleukin 2 receptor subunit alpha (IL2Rα) has been shown to influence immune responses. In the present research, using in silico techniques, we have demonstrated the potential IL2Rα binding properties of three polyphenol stilbenes (desoxyrhaponticin, rhaponticin, rhapontigenin) from fenugreek. As the first step, molecular docking was performed to assess the binding potential of the fenugreek phytochemicals with IL2Rα. All three phytochemicals demonstrated interactions with active site residues. To confirm the reliability of our molecular docking results, 100 ns molecular dynamics simulations studies were undertaken. As discerned by the RMSD and RMSF analyses, IL2Rα in complex with the desoxyrhaponticin, rhaponticin, and rhapontigenin indicated stability. The RMSD analysis of the phytochemicals alone also demonstrated no significant structural changes. Based on the stable molecular interactions and comparatively slightly better MM/PBSA binding free energy, rhaponticin seems promising. Additionally, ADMET analysis performed for the stilbenes indicated that all of them obey the ADMET rules. Our computational study thus supports further in vitro IL2Rα binding studies on these stilbenes, especially rhaponticin.     

A fluorescence displacement assay for antidepressant drug discovery based on ligand-conjugated quantum dots

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) protein plays a central role in terminating 5-HT neurotransmission and is the most important therapeutic target for the treatment of major depression and anxiety disorders. We report an innovative, versatile, and target-selective quantum dot (QD) labeling approach for SERT in single Xenopus oocytes that can be adopted as a drug-screening platform. Our labeling approach employs a custom-made, QD-tagged indoleamine derivative ligand, IDT318, that is structurally similar to 5-HT and accesses the primary binding site with enhanced human SERT selectivity. Incubating QD-labeled oocytes with paroxetine (Paxil), a high-affinity SERT-specific inhibitor, showed a concentration- and time-dependent decrease in QD fluorescence, demonstrating the utility of our approach for the identification of SERT modulators. Furthermore, with the development of ligands aimed at other pharmacologically relevant targets, our approach may potentially form the basis for a multitarget drug discovery platform.     

Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.     

In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-β-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.     

The Antagonist pGlu-βGlu-Pro-NH2 Binds to an Allosteric Site of the Thyrotropin-Releasing Hormone Receptor

After we identified pGlu-βGlu-Pro-NH₂ as the first functional antagonist of the cholinergic central actions of the thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH₂), we became interested in finding the receptor-associated mechanism responsible for this antagonism. By utilizing a human TRH receptor (hTRH-R) homology model, we first refined the active binding site within the transmembrane bundle of this receptor to enhance TRH’s binding affinity. However, this binding site did not accommodate the TRH antagonist. This directed us to consider a potential allosteric binding site in the extracellular domain (ECD). Searches for ECD binding pockets prompted the remodeling of the extracellular loops and the N-terminus. We found that different trajectories of ECDs produced novel binding cavities that were then systematically probed with TRH, as well as its antagonist. This led us to establish not only a surface-recognition binding site for TRH, but also an allosteric site that exhibited a selective and high-affinity binding for pGlu-βGlu-Pro-NH₂. The allosteric binding of this TRH antagonist is more robust than TRH’s binding to its own active site. The findings reported here may shed light on the mechanisms and the multimodal roles by which the ECD of a TRH receptor is involved in agonist and/or antagonist actions.     

Adsorption/Desorption Behaviors and SERS Chemical Enhancement of 6-Mercaptopurine on a Nanostructured Gold Surface: The Au20 Cluster Model

Computational approaches are employed to elucidate the binding mechanism and the SERS phenomenon of 6-mercaptopurine (6MP) adsorbed on the tetrahedral Au₂₀ cluster as a simple model for a nanostructured gold surface. Computations are carried out in both vacuum and aqueous environments using a continuum model. In the gaseous phase and neutral conditions, interaction of 6MP with the gold cluster is mostly dominated by a covalent Au−S bond and partially stabilized by the Au⋅⋅⋅H−N coupling. However, in acidic solution, the nonconventional Au⋅⋅⋅H−S hydrogen-bond becomes the most favorable binding mode. The 6MP affinity for gold clusters decreases in the order of vacuum > neutral solution > acidic medium. During the adsorption, the energy gap of Au₂₀ substantially declines, leading to an increase in its electrical conductivity, which can be converted to an electrical noise. Moreover, such interaction is likely a reversible process and triggered by either the low pH in sick tissues or the presence of cysteine residues in protein matrices. While N−H bending and stretching vibrations play major roles in the SERS phenomenon of 6MP on gold surfaces in neutral solution, the strongest enhancement in acidic environment is mostly due to an Au⋅⋅⋅H−S coupling, rather than an aromatic ring-gold surface π overlap as previously proposed.     

Chalcone Scaffolds Exhibiting Acetylcholinesterase Enzyme Inhibition: Mechanistic and Computational Investigations

This study was aimed to perform the mechanistic investigations of chalcone scaffold as inhibitors of acetylcholinesterase (AChE) enzyme using molecular docking and molecular dynamics simulation tools. Basic chalcones (C1–C5) were synthesized and their in vitro AChE inhibition was tested. Binding interactions were studied using AutoDock and Surflex-Dock programs, whereas the molecular dynamics simulation studies were performed to check the stability of the ligand–protein complex. Good AChE inhibition (IC₅₀ = 22 ± 2.8 to 37.6 ± 0.75 μM) in correlation with the in silico results (binding energies = −8.55 to −8.14 Kcal/mol) were obtained. The mechanistic studies showed that all of the functionalities present in the chalcone scaffold were involved in binding with the amino acid residues at the binding site through hydrogen bonding, π–π, π–cation, π–sigma, and hydrophobic interactions. Molecular dynamics simulation studies showed the formation of stable complex between the AChE enzyme and C4 ligand.     

Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp³ carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.     

Dual XH–π Interaction of Hexafluoroisopropanol with Arenes

The dual XH (OH and CH) hydrogen-bond-donating property of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and the strong dual XH–π interaction with arenes were firstly disclosed by theoretical studies. Here, the high accuracy post-Hartree–Fock methods, CCSD(T)/CBS, reveal the interaction energy of HFIP/benzene complex (−7.22 kcal/mol) and the contribution of the electronic correlation energy in the total interaction energy. Strong orbital interaction between HFIP and benzene was found by using the DFT method in this work to disclose the dual XH–π intermolecular orbital interaction of HFIP with benzene-forming bonding and antibonding orbitals resulting from the orbital symmetry of HFIP. The density of states and charge decomposition analyses were used to investigate the orbital interactions. Isopropanol (IP), an analogue of HFIP, and chloroform (CHCl₃) were studied to compare them with the classical OH–π, and non-classical CH–π interactions. In addition, the influence of the aggregating effect of HFIP, and the numbers of substituted methyl groups in benzene rings were also studied. The interaction energies of HFIP with the selected 24 common organic compounds were calculated to understand the role of HFIP as solvent or additive in organic transformation in a more detailed manner. A single-crystal X-ray diffraction study of hexafluoroisopropyl benzoate further disclosed and confirmed that the CH of HFIP shows the non-classical hydrogen-bond-donating behavior.     

Unraveling the Compositional and Molecular Features Involved in Lysozyme-Benzothiazole Derivative Interactions

In this work we present a computational analysis together with experimental studies, focusing on the interaction between a benzothiazole (BTS) and lysozyme. Results obtained from isothermal titration calorimetry, UV-vis, and fluorescence were contrasted and complemented with molecular docking and machine learning techniques. The free energy values obtained both experimentally and theoretically showed excellent similarity. Calorimetry, UV-vis, and 3D/2D-lig-plot analysis revealed that the most relevant interactions between BTS and lysozyme are based on a predominance of aromatic, hydrophobic Van der Waals interactions, mainly aromatic edge-to-face (T-shaped) π-π stacking interactions between the benzene ring belonging to the 2-(methylthio)-benzothiazole moiety of BTS and the aromatic amino acid residue TRP108 of the lysozyme receptor. Next, conventional hydrogen bonding interactions contribute to the stability of the BTS-lysozyme coupling complex. In addition, mechanistic approaches performed using elastic network models revealed that the BTS ligand theoretically induces propagation of allosteric signals, suggesting non-physiological conformational flexing in large blocks of lysozyme affecting α-helices. Likewise, the BTS ligand interacts directly with allosteric residues, inducing perturbations in the conformational dynamics expressed as a moderate conformational softening in the α-helices H1, H2, and their corresponding β-loop in the lysozyme receptor, in contrast to the unbound state of lysozyme.     

A convenient biomimetic synthesis of optically active putative neurotoxic metabolites of MDMA ("ecstasy") from R-(-)- and S-(+)-N-methyl-α-methyldopamine precursors

(±)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates. As yet, chirality of MDMA was not considered in previously reported in vivo studies because HHMA was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the total synthesis of enantiomerically pure precursors, R-(-)-HHMA and S-(+)-HHMA, was envisioned with the ultimate goal to prepare substantial amounts of optically active thioether conjugates. Recently, we reported the first total synthesis of the R-enantiomer. In this paper, a novel synthesis of the S-enantiomer is described, in 45% overall yield (six steps) and 99% ee, using commercially available l-Boc-alanine (99% ee) as the chiral source. Having at our disposal suitable amounts of R-(-)-HHMA and S-(+)-HHMA precursors, a straightforward one-pot electrochemical procedure has been further developed for the synthesis of several catechol-thioether conjugates in acceptable yields (40-53%) and high degree of purity (99%), with complete diastereoselectivity. The availability of these newly synthesized optically active catechol-thioether conjugates is crucial for ongoing future in vivo studies about their role in MDMA neurotoxicity.     

Targeting cell surface receptors with ligand-conjugated nanocrystals

To explore the potential for use of ligand-conjugated nanocrystals to target cell surface receptors, ion channels, and transporters, we explored the ability of serotonin-labeled CdSe nanocrystals (SNACs) to interact with antidepressant-sensitive, human and Drosophila serotonin transporters (hSERT, dSERT) expressed in HeLa and HEK-293 cells. Unlike unconjugated nanocrystals, SNACs were found to dose-dependently inhibit transport of radiolabeled serotonin by hSERT and dSERT, with an estimated half-maximal activity (EC(50)) of 33 (dSERT) and 99 microM (hSERT). When serotonin was conjugated to the nanocrystal through a linker arm (LSNACs), the EC(50) for hSERT was determined to be 115 microM. Electrophysiology measurements indicated that LSNACs did not elicit currents from the serotonin-3 (5HT(3)) receptor but did produce currents when exposed to the transporter, which are similar to those elicited by antagonists. Moreover, fluorescent LSNACs were found to label SERT-transfected cells but did not label either nontransfected cells or transfected cells coincubated with the high-affinity SERT antagonist paroxetine. These findings support further consideration of ligand-conjugated nanocrystals as versatile probes of membrane proteins in living cells.     

Computational and biological studies of novel thiazolyl coumarin derivatives synthesized through Suzuki coupling

The current investigation presents the synthesis, computational molecular-docking and biological activity studies of arylated thiazole coumarins. Aryl substituted thiazolyl coumarin derivatives were synthesized via Suzuki cross-coupling reaction. A detailed reaction condition optimization revealed that the Pd-PEPPSI-IPent precatalyst in only 2 mol% loading resulted in the desired product with high yield. The aim of this study was to examine the antimicrobial behavior of thiazole coumarin derivatives through in vitro and in silico studies. All the compounds showed activity against both antibacterial strains, Staphylococcus aureus and Escherichia coli, except 5d . Similarly, the compounds 5a , 5b , and 5d were found to be active against Trichoderma harzianum. The compound 5d of this series was found to have a higher activity with MIC 125 mg/ml against Trichoderma harzianum. Molecular studies showed the high activities of these compounds are due to the presence of strong H-bonding and π-π interaction with their respective targets. A good correlation was observed between computational and in vitro studies.     

Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia

Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC₅₀ value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (K_D) value of 5.529 × 10⁻⁵ M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.     

Interactions between Human Serum Albumin and Sulfadimethoxine Determined Using Spectroscopy and Molecular Docking

Sulfonamides are widely used antibiotics in agricultural production. However, the potential threat of these drugs to human health has increased global concern. Human serum albumin (HSA) is the main reservoir and transporter of exogenous small molecules in humans. In this study, the interaction between sulfadimethoxine (SMT) and human serum albumin (HSA) was studied using spectroscopy and computer simulation. Our results showed that the hydrogen bonding and van der Waals forces drove SMT to enter the binding site I of HSA spontaneously and resulted in the fluorescence quenching of HSA. The stability of the HSA–SMT complex decreased with an increase in temperature. The binding of SMT to HSA induced alterations in the secondary structure of HSA, where the content of α-helix decreased from 61.0% of the free state to 59.0% of the compound state. The π–π, π–σ, and π–alkyl interactions between HSA and SMT were found to play important roles in maintaining the stability of the complex.     

Toxic Effect of Fullerene and Its Derivatives upon the Transmembrane β2-Adrenergic Receptors

Numerous experiments have revealed that fullerene (C₆₀) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the β₂-adrenergic receptor (β₂AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of β₂AR through hydrophobic interactions and π–π stacking interactions. In the C₆₀_in1 trajectory, due to the π–π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of β₂AR. The hydroxyl groups of fullerene derivatives (C₆₀(OH)_X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of β₂AR. The hydroxyl groups firmly grasp the β₂AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of β₂AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C₆₀ did not compete with ligands for binding sites, but blocked the ligands’ entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity.     

Hydrogen and Lithium Bonds—Lewis Acid Units Possessing Multi-Center Covalent Bonds

MP2/aug-cc-pVTZ calculations were carried out on complexes wherein the proton or the lithium cation is located between π-electron systems, or between π-electron and σ-electron units. The acetylene or its fluorine and lithium derivatives act as the Lewis base π-electron species similarly to molecular hydrogen, which acts as the electron donor via its σ-electrons. These complexes may be classified as linked by π-H∙∙∙π/σ hydrogen bonds and π-Li∙∙∙π/σ lithium bonds. The properties of these interactions are discussed, and particularly the Lewis acid units are analyzed, because multi-center π-H or π-Li covalent bonds may occur in these systems. Various theoretical approaches were applied here to analyze the above-mentioned interactions—the Quantum Theory of Atoms in Molecules (QTAIM), the Symmetry-Adapted Perturbation Theory (SAPT) and the Non-Covalent Interaction (NCI) method.