Toxicity and Estrogenicity of Bisphenol TMC in Oryzias melastigma via In Vivo and In Silico Studies.

Bisphenol 4-[1-(4-hydroxyphenyl)-3,3,5-trimethylcyclohexyl] phenol (BPTMC), as a substitute for bisphenol A, has been detected in environments. However, the ecotoxicological data of BPTMC are extremely scarce. Here, the lethality, developmental toxicity, locomotor behavior, and estrogenic activity of BPTMC at different concentrations (0.25-2000 µg/L) in marine medaka (Oryzias melastigma) embryos were examined. In addition, the in silico binding potentials of O. melastigma estrogen receptors (omEsrs) with BPTMC were assessed by docking study. Low-concentration BPTMC exposure (including an environmentally relevant concentration, 0.25 µg/L) resulted in stimulating effects, including hatching rate, heart rate, malformation rate, and swimming velocity. However, elevated concentrations of BPTMC led to an inflammatory response, changed heart rate and swimming velocity in the embryos and larvae. In the meantime, BPTMC (including 0.25 µg/L) altered the concentrations of estrogen receptor, vitellogenin, and endogenous 17 ß-estradiol as well as the transcriptional levels of estrogen-responsive genes in the embryos or/and larvae. Furthermore, elaborate tertiary structures of omEsrs were built by ab initio modeling, and BPTMC exerted potent binding potential with three omEsrs with -47.23, -49.23, and -50.30 kJ/mol for Esr1, Esr2a, and Esr2b, respectively. This work suggests that BPTMC has potent toxicity and estrogenic effects in O. melastigma.

Fibrillization Process of Human Amyloid-Beta Protein (1-40) under a Molecular Crowding Environment Mimicking the Interior of Living Cells Using Cell Debris.

Molecular crowding environments play a crucial role in understanding the mechanisms of biological reactions. Inside living cells, a diverse array of molecules coexists within a volume fraction ranging from 10% to 30% v/v. However, conventional spectroscopic methods often face difficulties in selectively observing the structures of particular proteins or membranes within such molecularly crowded environments due to the presence of high background signals. Therefore, it is crucial to establish in vitro measurement conditions that closely resemble the intracellular environment. Meanwhile, the neutron scattering method offers a significant advantage in selectively observing target biological components, even within crowded environments. Recently, we have demonstrated a novel scattering method capable of selectively detecting the structures of targeted proteins or membranes in a closely mimicking intracellular milieu achieved utilizing whole-cell contents (deuterated-cell debris). This method relies on the inverse contrast matching technique in neutron scattering. By employing this method, we successfully observed the fibrillization process of human amyloid beta-protein (Aß 1-40) under a molecular crowding environment (13.1% w/v cell debris, Aß/cell debris = ~1/25 w/w) that closely mimics the interior of living cells. Aß protein is well known as a major pathogenic component of Alzheimer's disease. The present results combining model simulation analyses clearly show that the intracellular environment facilitates the potential formation of even more intricate higher-order aggregates of Aß proteins than those previously reported.

Solution Structure, Self-Assembly, and Membrane Interactions of the Matrix Protein from Newcastle Disease Virus at Neutral and Acidic pH.

Newcastle disease virus (NDV) is an enveloped paramyxovirus. The matrix protein of the virus (M-NDV) has an innate propensity to produce virus-like particles budding from the plasma membrane of the expressing cell without recruiting other viral proteins. The virus predominantly infects the host cell via fusion with the host plasma membrane or, alternatively, can use receptor-mediated endocytic pathways. The question arises as to what are the mechanisms supporting such diversity, especially concerning the assembling and membrane binding properties of the virus protein scaffold under both neutral and acidic pH conditions. Here, we suggest a novel method of M-NDV isolation in physiological ionic strength and employ a combination of small-angle X-ray scattering, atomic force microscopy with complementary structural techniques, and membrane interaction measurements to characterize the solution behavior/structure of the protein as well as its binding to lipid membranes at pH 4.0 and pH 7.0. We demonstrate that the minimal structural unit of the protein in solution is a dimer that spontaneously assembles in a neutral milieu into hollow helical oligomers by repeating the protein tetramers. Acidic pH conditions decrease the protein oligomerization state to the individual dimers, tetramers, and octamers without changing the density of the protein layer and lipid membrane affinity, thus indicating that the endocytic pathway is a possible facilitator of NDV entry into a host cell through enhanced scaffold disintegration.IMPORTANCE The matrix protein of the Newcastle disease virus (NDV) is one of the most abundant viral proteins that regulates the formation of progeny virions. NDV is an avian pathogen that impacts the economics of bird husbandry due to its resulting morbidity and high mortality rates. Moreover, it belongs to the Avulavirus subfamily of the Paramyxoviridae family of Mononegavirales that include dangerous representatives such as respiratory syncytial virus, human parainfluenza virus, and measles virus. Here, we investigate the solution structure and membrane binding properties of this protein at both acidic and neutral pH to distinguish between possible virus entry pathways and propose a mechanism of assembly of the viral matrix scaffold. This work is fundamental for understanding the mechanisms of viral entry as well as to inform subsequent proposals for the possible use of the virus as an adequate template for future drug or vaccine delivery.

Aggregate-State Effects in the Atomistic Modeling of Organic Materials for Electrochemical Energy Conversion and Storage Devices: A Perspective.

Development of new functional materials for novel energy conversion and storage technologies is often assisted by ab initio modeling. Specifically, for organic materials, such as electron and hole transport materials for perovskite solar cells, LED (light emitting diodes) emitters for organic LEDs (OLEDs), and active electrode materials for organic batteries, such modeling is often done at the molecular level. Modeling of aggregate-state effects is onerous, as packing may not be known or large simulation cells may be required for amorphous materials. Yet aggregate-state effects are essential to estimate charge transport rates, and they may also have substantial effects on redox potentials (voltages) and optical properties. This paper summarizes recent studies by the author's group of aggregation effects on the electronic properties of organic materials used in optoelectronic devices and in organic batteries. We show that in some cases it is possible to understand the mechanism and predict specific performance characteristics based on simple molecular models, while in other cases the inclusion of effects of aggregation is essential. For example, it is possible to understand the mechanism and predict the overall shape of the voltage-capacity curve for insertion-type organic battery materials, but not the absolute voltage. On the other hand, oligomeric models of p-type organic electrode materials can allow for relatively reliable estimates of voltages. Inclusion of aggregate state modeling is critically important for estimating charge transport rates in materials and interfaces used in optoelectronic devices or when intermolecular charge transfer bands are important. We highlight the use of the semi-empirical DFTB (density functional tight binding) method to simplify such calculations.

Large scale ab initio modeling of structurally uncharacterized antimicrobial peptides reveals known and novel folds.

Antimicrobial resistance within a wide range of infectious agents is a severe and growing public health threat. Antimicrobial peptides (AMPs) are among the leading alternatives to current antibiotics, exhibiting broad spectrum activity. Their activity is determined by numerous properties such as cationic charge, amphipathicity, size, and amino acid composition. Currently, only around 10% of known AMP sequences have experimentally solved structures. To improve our understanding of the AMP structural universe we have carried out large scale ab initio 3D modeling of structurally uncharacterized AMPs that revealed similarities between predicted folds of the modeled sequences and structures of characterized AMPs. Two of the peptides whose models matched known folds are Lebocin Peptide 1A (LP1A) and Odorranain M, predicted to form ß-hairpins but, interestingly, to lack the intramolecular disulfide bonds, cation-π or aromatic interactions that generally stabilize such AMP structures. Other examples include Ponericin Q42, Latarcin 4a, Kassinatuerin 1, Ceratotoxin D, and CPF-B1 peptide, which have α-helical folds, as well as mixed αß folds of human Histatin 2 peptide and Garvicin A which are, to the best of our knowledge, the first linear αßß fold AMPs lacking intramolecular disulfide bonds. In addition to fold matches to experimentally derived structures, unique folds were also obtained, namely for Microcin M and Ipomicin. These results help in understanding the range of protein scaffolds that naturally bear antimicrobial activity and may facilitate protein design efforts towards better AMPs.

Solution scattering approaches to dynamical ordering in biomolecular systems.

Clarification of solution structure and its modulation in proteins and protein complexes is crucially important to understand dynamical ordering in macromolecular systems. Small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS) are among the most powerful techniques to derive structural information. Recent progress in sample preparation, instruments and software analysis is opening up a new era for small-angle scattering. In this review, recent progress and trends of SAXS and SANS are introduced from the point of view of instrumentation and analysis, touching on general features and standard methods of small-angle scattering. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato.

Global shapes of F-actin depolymerization-competent minimal gelsolins: insight into the role of g2-g3 linker in pH/Ca2+ insensitivity of the first half.

Because of its ability to rapidly depolymerize F-actin, plasma gelsolin has emerged as a therapeutic molecule in different disease conditions. High amounts of exogenous gelsolin are, however, required to treat animal models of different diseases. Knowing that the F-actin depolymerizing property of gelsolin resides in its N terminus, we made several truncated versions of plasma gelsolin. The smaller versions, particularly the one composed of the first 28-161 residues, depolymerized the F-actin much faster than the native gelsolin and other truncates at the same molar ratios. Although G1-G3 loses its dependence on Ca(2+) or low pH for the actin depolymerization function, interestingly, G1-G2 and its smaller versions were found to regain this requirement. Small angle x-ray scattering-based shape reconstructions revealed that G1-G3 adopts an open shape in both the presence and the absence of Ca(2+) as well as low pH, whereas G1-G2 and residues 28-161 prefer collapsed states in Ca(2+)-free conditions at pH 8. The mutations in the g2-g3 linker resulted in the calcium sensitivity of the mutant G1-G3 for F-actin depolymerization activity, although the F-actin-binding sites remained exposed in the mutant G1-G3 as well as in the smaller truncates even in the Ca(2+)-free conditions at pH 8. Furthermore, unlike wild type G1-G3, calcium-sensitive mutants of G1-G3 acquired closed shapes in the absence of free calcium, implying a role of g2-g3 linker in determining the open F-actin depolymerizing-competent shape of G1-G3 in this condition. We demonstrate that the mobility of the G1 domain, essential for F-actin depolymerization, is indirectly regulated by the gelsolin-like sequence of g2-g3 linker.

Insights on the dynamic behavior of protein disulfide isomerase in the solution environment through the SAXS technique.

The dynamic behavior of Protein Disulfide Isomerase (PDI) in an aqueous solution environment under physiologically active pH has been experimentally verified in this study using Small Angle X-ray Scattering (SAXS) technique. The structural mechanism of dimerization for full-length PDI molecules and co-complex with two renowned substrates has been comprehensively discussed. The structure models obtained from the SAXS data of PDI purified from bovine liver display behavior duality between unaccompanied-enzyme and after engaged with substrates. The analysis of SAXS data revealed that PDI exists as a homo-dimer in the solution environment, and substrate induction provoked its segregation into monomer to enable the enzyme to interact systematically with incoming clients. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00198-0.

A homology/ab initio hybrid algorithm for sampling near-native protein conformations.

One of the major challenges for protein tertiary structure prediction strategies is the quality of conformational sampling algorithms, which can effectively and readily search the protein fold space to generate near-native conformations. In an effort to advance the field by making the best use of available homology as well as fold recognition approaches along with ab initio folding methods, we have developed Bhageerath-H Strgen, a homology/ab initio hybrid algorithm for protein conformational sampling. The methodology is tested on the benchmark CASP9 dataset of 116 targets. In 93% of the cases, a structure with TM-score ≥ 0.5 is generated in the pool of decoys. Further, the performance of Bhageerath-H Strgen was seen to be efficient in comparison with different decoy generation methods. The algorithm is web enabled as Bhageerath-H Strgen web tool which is made freely accessible for protein decoy generation (http://www.scfbio-iitd.res.in/software/Bhageerath-HStrgen1.jsp).

Theoretical Prediction of the Sublimation Behavior by Combining Ab Initio Calculations with Statistical Mechanics.

We develop a theoretical model to predict the sublimation vapor pressure of pure substances. Moreover, we present a simple monoatomic molecule approximation, which reduces the complexity of the vapor pressure expression for polyatomic gaseous molecules at a convincing level of accuracy, with deviations of the Arrhenius prefactor for NaCl and NaF being 5.02% and 7.08%, respectively. The physical model is based on ab initio calculations, statistical mechanics, and thermodynamics. We illustrate the approach for Ni, Cr, Cu (metallic bond), NaCl, NaF, ZrO2 (ionic bond) and SiO2 (covalent bond). The results are compared against thermodynamic databases, which show high accuracy of our theoretical predictions, and the deviations of the predicted sublimation enthalpy are typically below 10%, for Cu even only 0.1%. Furthermore, the partial pressures caused by gas phase reactions are also explored, showing good agreement with experimental results.

In silico structural analysis of secretory clusterin to assess pathogenicity of mutations identified in the evolutionarily conserved regions.

Clusterin (CLU) is a secreted glycoprotein, heterodimeric in nature, and is expressed in a wide variety of tissues and body fluids such as serum and plasma. CLU has also been known to be a promising biomarker for cell death, malignancy, cancer progression, and resistance development. However, the lack of a CLU crystal structure obstructs understanding the possible role of reported mutations on the structure, and the subsequent effects on downstream signaling pathways and cancer progression. Considering the importance of crystal structure, a model structure of the pre-secretory isoform of CLU was built to predict the effect of mutations at the molecular level. Ab initio model was built using RaptorX, and loop refinement and energy minimization were carried out with ModLoop, ModRefiner, and GalaxyWeb servers. The cancer associated mutational spectra of CLU was retrieved from the cBioPortal server and 117 unique missense mutations were identified. Evolutionarily conserved regions and pathogenicity of mutations identified in CLU were analyzed using ConSurf and Rhapsody, respectively. Furthermore, sequence and structure-based mutational analysis were carried out with iSTABLE, DynaMut and PremPS servers. Molecular dynamics simulations were carried out with GROMACS for 50 ns to determine the stability of the wild type and mutant protein structures. A dynamically stable model structure of pre-secretory CLU (psCLU) which has high concurrence with the sequence based secondary structure predictions has been explored. Changes in the intra-atomic interactions and folding pattern between wild type and mutant structures were observed. To our conclusion, eleven mutations with the highest structural and functional significance have been predicted to have pathogenic and deleterious effects.Communicated by Ramaswamy H. Sarma.

Understanding palladium-tellurium cluster formation on WTe2: From a kinetically hindered distribution to thermodynamically controlled monodispersity.

A fundamental understanding of the transition metal dichalcogenide (TMDC)-metal interface is critical for their utilization in a broad range of applications. We investigate how the deposition of palladium (Pd), as a model metal, on WTe2(001), leads to the assembly of Pd into clusters and nanoparticles. Using X-ray photoemission spectroscopy, scanning tunneling microscopy imaging, and ab initio simulations, we find that Pd nucleation is driven by the interaction with and the availability of mobile excess tellurium (Te) leading to the formation of Pd-Te clusters at room temperature. Surprisingly, the nucleation of Pd-Te clusters is not affected by intrinsic surface defects, even at elevated temperatures. Upon annealing, the Pd-Te nanoclusters adopt an identical nanostructure and are stable up to ∼523 K. Density functional theory calculations provide a foundation for our understanding of the mobility of Pd and Te atoms, preferential nucleation of Pd-Te clusters, and the origin of their annealing-induced monodispersity. These results highlight the role the excess chalcogenide atoms may play in the metal deposition process. More broadly, the discoveries of synthetic pathways yielding thermally robust monodispersed nanostructures on TMDCs are critical to the manufacturing of novel quantum and microelectronics devices and catalytically active nano-alloy centers.

Effect of amphiphilic environment on the solution structure of mouse TSPO translocator protein.

The translocator protein (TSPO) is a ubiquitous transmembrane protein of great pharmacological interest thanks to its high affinity to many drug ligands. The only high-resolution 3D-structure known for mammalian TSPO was obtained by NMR for the mouse mTSPO in DPC detergent only in presence of the high-affinity PK 11195 ligand. An atomic structure of free-ligand mTSPO is still missing to better understand the interaction of ligands with mTSPO and their effects on the protein conformation. Here, we decipher the solution structures of the recombinant mTSPO without ligand both in (i) SDS, the detergent used to extract and purify the protein from E. coli inclusion bodies, and (ii) DPC, the detergent used to solve the PK 11195-binding mTSPO NMR structure. We report partially refolded and less flexible mTSPO helices in DPC compared to SDS. Besides, DPC stabilizes the tertiary structure of mTSPO, as shown by a higher intrinsic Trp fluorescence and changes in indole environment. We evaluate by SEC-MALLS that ∼135 SDS and ∼100 DPC molecules are bound to mTSPO. SEC-small-angle X-ray (SAXS) and neutron (SANS) scattering confirm a larger mTSPO-detergent complex in SDS than in DPC. Using the contrast-matching technique in SEC-SANS, we demonstrate that mTSPO conformation is more compact and less flexible in DPC than in SDS. Combining ab initio modeling with SANS, we confirm that mTSPO conformation is less elongated in DPC than in SDS. However, the free-ligand mTSPO envelope in DPC is not as compact as the PK 11195-binding protein NMR structure, the ligand stiffening the protein.

Illuminating the "Twilight Zone": Advances in Difficult Protein Modeling.

Homology modeling was long considered a method of choice in tertiary protein structure prediction. However, it used to provide models of acceptable quality only when templates with appreciable sequence identity with a target could be found. The threshold value was long assumed to be around 20-30%. Below this level, obtained sequence identity was getting dangerously close to values that can be obtained by chance, after aligning any random, unrelated sequences. In these cases, other approaches, including ab initio folding simulations or fragment assembly, were usually employed. The most recent editions of the CASP and CAMEO community-wide modeling methods assessment have brought some surprising outcomes, proving that much more clues can be inferred from protein sequence analyses than previously thought. In this chapter, we focus on recent advances in the field of difficult protein modeling, pushing the threshold deep into the "twilight zone", with particular attention devoted to improvements in applications of machine learning and model evaluation.

Modeling of Transmembrane Domain and Full-Length TLRs in Membrane Models.

Toll-like receptors (TLRs), classified as pattern recognition receptors, have a primordial role in the activation of the innate immunity. In particular, TLR4 binds to lipopolysaccharides (LPS), a membrane constituent of Gram-negative bacteria, and, together with Myeloid Differentiation factor 2 (MD-2) protein, forms a heterodimeric complex which leads to the activation of the innate immune system response. Identification of TLRs has sparked great interest in the therapeutic manipulation of the innate immune system. In particular, TLR4 antagonists may be useful for the treatment of septic shock, certain autoimmune diseases, noninfectious inflammatory disorders, and neuropathic pain, and TLR4 agonists are under development as vaccine adjuvants in antitumoral treatments. Therefore, TLR4 has risen as a promising therapeutic target, and its modulation constitutes a highly relevant and active research area. Deep structural understanding of TLR4 signaling may help in the design and discovery of TLR4-modulating molecules with desirable therapeutic properties.Computational studies of the different independent domains composing the TLR4 were undertaken, to understand the differential domain organization of TLR4 in aqueous and membrane environments, including Liquid-disordered (Ld) and Liquid-ordered (Lo) membrane models, to account for the TLR4 recruitment in lipid rafts over activation. We modeled, by means of all-atom Molecular Dynamics (MD) simulations, the structural assembly of plausible full-length TLR4 models embedded into a realistic plasma membrane, accounting for the active (agonist) state of the TLR4, thus providing an analysis at both atomic/molecular and thermodynamic levels of the TLR4 assembly and biological activity. Our results unveil relevant molecular aspects involved in the mechanism of receptor activation, and adaptor recruitment in the innate immune pathways, and will promote the discovery of new TLR4 modulators and probes.

Modeling of SARS-CoV-2 Virus Proteins: Implications on Its Proteome.

COronaVIrus Disease 19 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a group of beta coronaviruses, SARS-CoV-2. The SARS-CoV-2 virus is similar to previous SARS- and MERS-causing strains and has infected nearly six hundred and fifty million people all over the globe, while the death toll has crossed the six million mark (as of December, 2022). In this chapter, we look at how computational modeling approaches of the viral proteins could help us understand the various processes in the viral life cycle inside the host, an understanding of which might provide key insights in mitigating this and future threats. This understanding helps us identify key targets for the purpose of drug discovery and vaccine development.

Identification of multi-targeting natural antiviral peptides to impede SARS-CoV-2 infection.

SARS-CoV-2 and its variants cause serious health concerns throughout the world. The alarming increase in the daily number of cases has become a nightmare in many low-income countries; although some vaccines are available, their high cost and low vaccine production make them unreachable to ordinary people in developing countries. Other treatment strategies are required for novel therapeutic options. The peptide-based drug is one of the alternatives with low toxicity, more specificity, and ease of synthesis. Herein, we have applied structure-based virtual screening to identify potential peptides targeting the critical proteins of SARS-CoV-2. Non-toxic natural antiviral peptides were selected from the enormous number of peptides. Comparative modeling was applied to prepare a 3D structure of selected peptides. 3D models of the peptides were docked using the ClusPro docking server to determine their binding affinity and peptide-protein interaction. The high-scoring peptides were docked with other crucial proteins to analyze multiple targeting peptides. The two best peptides were subjected to MD simulations to validate the structure stability and evaluated RMSD, RMSF, Rg, SASA, and H-bonding from the trajectory analysis of 100 ns. The proposed lead peptides can be used as a broad-spectrum drug and potentially develop as a therapeutic to combat SARS-CoV-2, positively impacting the current pandemic. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02113-9.

Plasmon-Phonon Coupling in Electrostatically Gated ß-Ga2O3 Films with Mobility Exceeding 200 cm2 V-1 s-1.

Monoclinic ß-Ga2O3, an ultra-wide bandgap semiconductor, has seen enormous activity in recent years. However, the fundamental study of the plasmon-phonon coupling that dictates electron transport properties has not been possible due to the difficulty in achieving higher carrier density (without introducing chemical disorder). Here, we report a highly reversible, electrostatic doping of ß-Ga2O3 films with tunable carrier densities using ion-gel-gated electric double-layer transistor configuration. Combining temperature-dependent Hall effect measurements, transport modeling, and comprehensive mobility calculations using ab initio based electron-phonon scattering rates, we demonstrate an increase in the room-temperature mobility to 201 cm2 V-1 s-1 followed by a surprising decrease with an increasing carrier density due to the plasmon-phonon coupling. The modeling and experimental data further reveal an important "antiscreening" (of electron-phonon interaction) effect arising from dynamic screening from the hybrid plasmon-phonon modes. Our calculations show that a significantly higher room-temperature mobility of 300 cm2 V-1 s-1 is possible if high electron densities (>1020 cm-3) with plasmon energies surpassing the highest energy LO mode can be realized. As Ga2O3 and other polar semiconductors play an important role in several device applications, the fundamental understanding of the plasmon-phonon coupling can lead to the enhancement of mobility by harnessing the dynamic screening of the electron-phonon interactions.

New Insights into the Crystal Chemistry of Elpidite, Na2Zr[Si6O15]·3H2O and (Na1+YCax□1-X-Y)Σ=2Zr[Si6O15]·(3-X)H2O, and Ab Initio Modeling of IR Spectra.

Elpidite belongs to a special group of microporous zirconosilicates, which are of great interest due to their capability to uptake various molecules and ions, e.g., some radioactive species, in their structural voids. The results of a combined electron probe microanalysis and single-crystal X-ray diffraction study of the crystals of elpidite from Burpala (Russia) and Khan-Bogdo (Mongolia) deposits are reported. Some differences in the chemical compositions are observed and substitution at several structural positions within the structure of the compounds are noted. Based on the obtained results, a detailed crystal-chemical characterization of the elpidites under study was carried out. Three different structure models of elpidite were simulated: Na2ZrSi6O15·3H2O (related to the structure of Russian elpidite), partly Ca-replaced Na1.5Ca0.25ZrSi6O15·2.75H2O (close to elpidite from Mongolia), and a hypothetical CaZrSi6O15·2H2O. The vibration spectra of the models were obtained and compared with the experimental one, taken from the literature. The strong influence of water molecule vibrations on the shape of IR spectra of studied structural models of elpidite is discussed in the paper.

In Silico Identification of Potential Inhibitors of the Wnt Signaling Pathway in Human Breast Cancer.

Triple-negative breast cancer is the leading worldwide cause of cancer-related deaths in women. The prospection and development of new substances with antitumoral potential is of great importance for the treatment of this disease. The objective of this work was to identify a commercial drug or ligand that could potentially bind to the FZD7 transmembrane protein and inactivate the Wnt signaling pathway in triple-negative breast cancer cells. We aimed at computationally modeling the FZD7, Wnt3, and Wnt3a proteins, at making them available in protein model databases, and at conducting docking analysis to assess the binding free energy between FZD7 and the selected ligands. The Wnt3 and Wnt3a proteins were modeled by homology modeling, and the FZD7 protein was modeled by homology modeling and ab initio modeling. The ligands were selected based on their similarity to the palmitoleic acid and were gathered from the ZINC database. A total of 30 commercially available ligands were found in the ZINC database. The docking results show that the ligands zinc08221009, zinc13546050, zinc05260769, zinc04529321, and zinc05972969 are good candidates for novel drug development. The created models and conducted analysis by this work will most certainly help in future research on the Wnt signaling pathway and its components.