Identification of promising inhibitors against breast cancer disease by targeting NUDIX hydrolase 5 (NUDT5) biomolecule.

It is well documented that NUDT5 enzyme inhibition in breast cancer cell lines arrest cancer cells growth, invasiveness and migration. The NUDT5 enzyme enhances breast cancer aggressiveness and act as key regulator of oncogenic pathways. Similarly, the NUDT5 enzyme plays a primer role in ATP-dependent cellular processes and proliferation in breast cancer. Thus, the NUDT5 enzyme plays a profound contribution in promoting breast cancers carcinogenesis and could be an ideal target for anti-cancer drug discovery. In this work, LAS_51382001, LAS_51177972 and LAS_51380924 with binding energy of -12.64 kcal/mol, -11.59 kcal/mol and -10.01 kcal/mol, respectively were filtered as lead molecules. The control molecule binding energy was -10.87 kcal/mol. The system dynamics were found uniform in molecular dynamics simulation studies and observed with no major structural changes. Among the leads, the LAS_51177972 showed the most stable binding energy values. The MM-GBSA binding energy of the compound was -37.07 kcal/mol and MM-PBSA binding energy of -43.56 kcal/mol. Similarly, the compound revealed very stable WaterSwap absolute binding energy values; Bennett's, TI and FEP energy of -36.2 kcal/mol, -36.13 kcal/mol and -36.58 kcal/mol, respectively. Similarly, the leads reported very favorable physicochemical properties, water solubility, pharmacokinetics, druglikeness and medicinal chemistry properties. In a nutshell, the compounds are potent in term of the current computational study however, need to be subjected to experimental studies.Communicated by Ramaswamy H. Sarma.

Structural Dynamics of P-Rex1 Complexed with Natural Leads Establishes the Protein as an Attractive Target for Therapeutics to Suppress Cancer Metastasis.

Phosphatidylinositol 3,4,5-trisphosphate- (PIP3-) dependent Rac exchanger 1 (P-Rex1) functions as Rho guanine nucleotide exchange factor and is activated by synergistic activity of Gßγ and PIP3 of the heterotrimeric G protein. P-Rex1 activates Rac GTPases for regulating cell invasion and migration and promotes metastasis in several human cancers including breast, prostate, and skin cancer. The protein is a promising therapeutic target because of its multifunction roles in human cancers. Herein, the present study attempts to identify selective P-Rex1 natural inhibitors by targeting PIP3-binding pocket using large-size multiple natural molecule libraries. Each library was filtered subsequently in FAF-Drugs4 based on Lipinski's rule of five (RO5), toxicity, and filter pan assay interference compounds (PAINS). The output hits were virtually screened at the PIP3-binding pocket through PyRx AutoDock Vina and cross-checked by GOLD. The best binders at the PIP3-binding pocket were prioritized using a comparative analysis of the docking scores. Top-ranked two compounds with high GOLD fitness score (>80) and lowest AutoDock binding energy (< -12.7 kcal/mol) were complexed and deciphered for molecular dynamics along with control-P-Rex1 complex to validate compound binding conformation and disclosed binding interaction pattern. Both the systems were seen in good equilibrium, and along the simulation time, the compounds are in strong contact with the P-Rex1 PIP3-binding site. Hydrogen bonding analysis towards simulation end identified the formation of 16 and 22 short- and long-distance hydrogen bonds with different percent of occupancy to the PIP3 residues for compound I and compound 2, respectively. Radial distribution function (RDF) analysis of the key hydrogen bonds between the compound and the PIP3 residues demonstrated a strong affinity of the compounds to the mentioned PIP3 pocket. Additionally, MMGB/PBSA energies were performed that confirmed the dominance of Van der Waals energy in complex formation along with favorable contribution from hydrogen bonding. These findings were also cross-validated by a more robust WaterSwap binding energy predictor, and the results are in good agreement with a strong binding affinity of the compounds for the protein. Lastly, the key contribution of residues in interaction with the compounds was understood by binding free energy decomposition and alanine scanning methods. In short, the results of this study suggest that P-Rex1 is a good druggable target to suppress cancer metastasis; therefore, the screened druglike molecules of this study need in vitro and in vivo anti-P-Rex1 validation and may serve as potent leads to fight cancer.

Role of Mangiferin in Management of Cancers through Modulation of Signal Transduction Pathways.

Cancer is a major public health concern worldwide in terms of mortality. The exact reason behind the development of cancer is not understood clearly, but it is evidenced that alcohol consumption, radiation, and exposure to chemicals are main players in this pathogenesis. The current mode of treatments such as surgery, chemotherapy, and radiotherapy are effective, but, still, cancer is a major problem leading to death and other side effects. However, safer and effective treatment modules are needed to overcome the adverse effects of current treatment modules. In this regard, natural compounds have been recognized to ameliorate diseases by exerting anti-inflammatory, anti-oxidative, and anti-tumor potential through several mechanisms. Mangiferin, a xanthone C-glucoside, is found in several plant species including Mangifera indica (mango), and its role in disease prevention has been confirmed through its antioxidant and anti-inflammatory properties. Furthermore, its anti-cancer-potential mechanism has been designated through modulation of cell signaling pathways such as inflammation, angiogenesis, PI3K/AKT, apoptosis, and cell cycle. This article extensively reviews the anticancer potential of mangiferin in different cancers through the modulation of cell signaling pathways. Moreover, the synergistic effects of this compound with some commonly used anti-cancer drugs against different cancer cells are discussed. More clinical trials should be performed to reconnoiter the anti-cancer potential of this compound in human cancer treatment. Further, understanding of mechanisms of action and the safety level of this compound can help to manage diseases, including cancer.

Innovative Strategies of Reprogramming Immune System Cells by Targeting CRISPR/Cas9-Based Genome-Editing Tools: A New Era of Cancer Management.

The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed.

Venetoclax analogs as promising anticancer therapeutics via targeting Bcl-2 protein: in-silico drug discovery study.

B-cell lymphoma 2 (Bcl-2) protein plays a vital role in enhancing malignant cell survival by alleviating programmed cell death. Therefore, Bcl-2 protein has been identified as a charming druggable target for cancer treatment. Venetoclax has enticed considerable attention as a potential Bcl-2 inhibitor. Herein, in-silico computations were executed to search for new venetoclax analogs against the Bcl-2 protein. A library involving 4112 was collected, prepared, and virtually screened against Bcl-2 protein using AutoDock Vina1.1.2 software. Promising analogs in complex with Bcl-2 protein were further submitted to molecular dynamics (MD) simulations, pursued by binding energy computations using the MM-GBSA approach. Compared to venetoclax (ΔGbinding = -51.2 kcal/mol), PubChem-873-158-83 and PubChem-148-422-478 demonstrated greater binding affinities with Bcl-2 protein throughout 100 ns MD simulations with ΔGbinding values of -69.1 and -62.4 kcal/mol, respectively. Structural and energetical analyses unveiled good stabilization of the identified analogs complexed with Bcl-2 protein over the MD course. The pharmacokinetic features of the two identified analogs were anticipated and unveiled the oral bioavailability of these compounds. Further in-vitro/in-vivo biological evaluations around these compounds could assist in identifying anticancer leads towards Bcl-2 protein.Communicated by Ramaswamy H. Sarma.

In Silico Mining of Natural Products Atlas (NPAtlas) Database for Identifying Effective Bcl-2 Inhibitors: Molecular Docking, Molecular Dynamics, and Pharmacokinetics Characteristics.

The Bcl-2 protein has a vital function in controlling the programmed cell doom of mitochondria. If programmed cell death signals are obstructed, an imbalance between cell survival and death will occur, which is a significant reason for cancer. Therefore, the Bcl-2 protein was identified as a possible therapeutic target for carcinoma treatment. Herein, the Natural Products Atlas (NPAtlas) compounds were virtually screened, seeking potent inhibitors towards the Bcl-2 protein. The performance of AutoDock Vina software to predict the docking score and pose of the investigated compounds was first validated according to the available experimental data. Based on the validated AutoDock Vina parameters, the NPAtlas database was filtered against the Bcl-2 protein. The natural compounds with docking scores less than that of the venetoclax (calc. -10.6 kcal/mol) were submitted to MD simulations, followed by MM-GBSA binding energy calculations. According to MM-GBSA//200 ns MD simulations, saquayamycin F (NPA002200) demonstrated promising binding affinity with a ΔGbinding value of -53.9 kcal/mol towards the Bcl-2 protein when compared to venetoclax (ΔGbinding = -50.6 kcal/mol). The energetical and structural analyses showed a great constancy of the saquayamycin F inside the Bcl-2 protein active site. Moreover, the ADMET and drug-likeness features of the saquayamycin F were anticipated, indicating its good oral bioavailability. According to in silico computations, saquayamycin F is proposed to be used as a therapeutic agent against the wild-type Bcl-2 protein and warrants further experimental assays.

In silico drug repurposing and lipid bilayer molecular dynamics puzzled out potential breast cancer resistance protein (BCRP/ABCG2) inhibitors.

Multidrug resistance (MDR) is a fundamental reason for the fiasco of carcinoma chemotherapy. A wide variety of anticarcinoma drugs are expelled from neoplasm cells through the ATP-binding cassette (ABC) transporter superfamily, rendering the neoplasm cells resistant to treatment. The ATP-binding cassette transporter G2 (ABCG2, gene symbol BCRP) is an ABC efflux transporter that plays a key function in MDR to antineoplastic therapies. For these reasons, the identification of medicaments as BCRP inhibitors could assist in discovering better curative approaches for breast cancer therapy. Because of the deficiency of prospective BCRP inhibitors, the SuperDRUG2 database was virtually screened for inhibitor activity towards the BCRP transporter using molecular docking computations. The most potent drug candidates were then characterized utilizing molecular dynamics (MD) simulations. Furthermore, molecular mechanics-generalized Born surface area (MM-GBSA) binding affinities of the most potent drug candidates were estimated. Based on the MM-GBSA binding affinities throughout 150 ns MD simulations, three drugs-namely zotarolimus (SD002595), temsirolimus (SD003393), and glecaprevir (SD006009)-revealed greater binding affinities towards BCRP transporter compared to the co-crystallized BWQ ligand with ΔGbinding values of -86.6 ± 5.6, -79.5 ± 8.0, -75.8 ± 4.6 and -59.5 ± 4.1 kcal/mol, respectively. The steadiness of these promising drugs bound with BCRP transporter was examined utilizing their structural and energetical analyses throughout a 150 ns MD simulation. To imitate the physiological environment, 150 ns MD simulations for the identified drugs bound with BCRP transporter were conducted in the 1-palmitoyl-2-oleoyl-phosphatidylcholine lipid bilayer. These findings identify zotarolimus, temsirolimus and glecaprevir as auspicious anti-MDR drug leads that warrant further experimental assays.Communicated by Ramaswamy H. Sarma.

Immunoinformatics- and Bioinformatics-Assisted Computational Designing of a Novel Multiepitopes Vaccine Against Cancer-Causing Merkel Cell Polyomavirus.

Merkel cell polyomavirus (MCV) contains double-stranded DNA as its genome and is the fifth polyomavirus that infects humans. The virus causes Merkel cell carcinoma (aggressive skin cancer). Till present, no proper drug or vaccines are available to treat/prevent the virus infection and stop the emergence of Merkel cell carcinoma. In this study, computational vaccine design strategies were applied to design a chimeric-epitopes vaccine against the virus. The complete proteome comprised of four proteins was filtered through various vaccine candidacy parameters and as such two proteins, namely, capsid protein VP1 and capsid protein VP2, were considered as good vaccine targets. Furthermore, they harbor safe and potential B and T cell epitopes, which can be used in a chimeric multiepitopes-based vaccine design. The epitopes of the vaccine have maximum world population coverage of 95.04%. The designed vaccine structure was modeled in 3D that reported maximum residues in favored regions (95.7%) of the Ramachandran plot. The interactions analysis with different human immune receptors like TLR3, MHC-I, and MHC-II illustrated vaccine's good binding affinity and stable dynamics. The structural deviations of the vaccine receptor(s) complexes are within 5 Å, where majority of the receptors residues remain in good equilibrium in the simulation time. Also, the vaccine was found to form between 60 and 100 hydrogen bonds to receptors. The vaccine stimulated strong immune responses in addition to interferon and cytokines. The strength of vaccine-receptor(s) binding was further affirmed by binding energies estimation that concluded <-150.32 kcal/mol of net binding energy. All these findings suggest the vaccine as a promising candidate that needs further experimental testing to disclose its real immune protective efficacy. Furthermore, the designed vaccine might accelerate vaccine development against the MCV and could save time and expenses.

Lipid-Based Nanoparticle Formulation of Diallyl Trisulfide Chemosensitizes the Growth Inhibitory Activity of Doxorubicin in Colorectal Cancer Model: A Novel In Vitro, In Vivo and In Silico Analysis.

Garlic's main bioactive organosulfur component, diallyl trisulfide (DATS), has been widely investigated in cancer models. However, DATS is not suitable for clinical use due to its low solubility. The current study seeks to improve DATS bioavailability and assess its chemopreventive and chemosensitizing properties in an AOM-induced colorectal cancer model. The polyethylene glycol coated Distearoylphosphatidylcholine/Cholesterol (DSPC/Chol) comprising DATS-loaded DATSL and doxorubicin (DOXO)-encapsulated DOXL liposomes was prepared and characterized. The changes in the sensitivity of DATS and DOXO by DATSL and DOXL were evaluated in RKO and HT-29 colon cancer cells. The synergistic effect of DATSL and DOXL was studied by cell proliferation assay in the combinations of IC10, IC25, and IC35 of DATSL with the IC10 of DOXL. AOM, DATSL, and DOXL were administered to different groups of mice for a period of 21 weeks. The data exhibited ~93% and ~46% entrapment efficiency of DATSL and DOXL, respectively. The size of sham liposomes was 110.5 nm, whereas DATSL and DOXL were 135.5 nm and 169 nm, respectively. DATSL and DOXL exhibited significant sensitivity in the cell proliferation experiment, lowering their IC50 doses by more than 8- and 14-fold, respectively. However, the DATSL IC10, IC25, and IC35 showed escalating chemosensitivity, and treated the cells in combination with DOXL IC10. Analysis of histopathological, cancer marker enzymes, and antioxidant enzymes revealed that the high dose of DATSL pretreatment and DOXL chemotherapy is highly effective in inhibiting AOM-induced colon cancer promotion. The combination of DATSL and DOXL indicated promise as a colorectal cancer treatment in this study. Intermolecular interactions of DATS and DOXO against numerous cancer targets by molecular docking indicated MMP-9 as the most favourable target for DATS exhibiting binding energy of -4.6 kcal/mol. So far, this is the first research to demonstrate the chemopreventive as well as chemosensitizing potential of DATSL in an animal model of colorectal cancer.

Naturally occurring plant-based anticancerous candidates as prospective ABCG2 inhibitors: an in silico drug discovery study.

ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. - 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (- 100.4, - 94.7, and - 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed.

Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence.

Triple-negative breast cancer (TNBC) is a kind of breast cancer that lacks estrogen, progesterone, and human epidermal growth factor receptor 2. This cancer is responsible for more than 15-20% of all breast cancers and is of particular research interest as it is therapeutically challenging mainly because of its low response to therapeutics and highly invasive nature. The non-availability of specific treatment options for TNBC is usually managed by conventional therapy, which often leads to relapse. The focus of this review is to provide up-to-date information related to TNBC epidemiology, risk factors, metastasis, different signaling pathways, and the pathways that can be blocked, immune suppressive cells of the TNBC microenvironment, current and investigation therapies, prognosis, and the role of artificial intelligence in TNBC diagnosis. The data presented in this paper may be helpful for researchers working in the field to obtain general and particular information to advance the understanding of TNBC and provide suitable disease management in the future.

In Silico Targeting Human Multidrug Transporter ABCG2 in Breast Cancer: Database Screening, Molecular Docking, and Molecular Dynamics Study.

ABCG2 is a substantial member of the ABC transporter superfamily that plays a significant role in multidrug resistance in cancer. Until recently, the 3D structure of ABCG2 has not been resolved, which resulted in the limitation of developing potential ABCG2 inhibitors using structure-based drug discovery. Herein, eMolecules, ChEMBL, and ChEBI databases, containing >25 million compounds, were virtually screened against the ABCG2 transporter in homodimer form. Performance of AutoDock4.2.6 software to predict inhibitor-ABCG2 binding mode and affinity were validated on the basis of available experimental data. The explored databases were filtered based on docking scores. The most potent hits with binding affinities higher than that of experimental bound ligand (MZ29) were then selected and subjected to molecular mechanics minimization, followed by binding energy calculation using molecular mechanics-generalized Born surface area (MM-GBSA) approach. Furthermore, molecular dynamics simulations for 50 ns, followed by MM-GBSA binding energy calculations, were performed for the promising compounds, unveiling eight potential inhibitors with binding affinities <-55.8 kcal/mol. Structural and energetic analyses demonstrated the stability of the eight identified inhibitors over the 50 ns MD simulation. This research sheds light on the potentiality of the identified ABCG2 inhibitors as a therapeutic approach to overcome multidrug resistance cancer therapy.

Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase.

As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, - 54.8 and - 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.

Prospective Drug Candidates as Human Multidrug Transporter ABCG2 Inhibitors: an In Silico Drug Discovery Study.

Breast cancer resistance protein (ABCG2) is a human ATP-binding cassette (ABC) that plays a paramount role in multidrug resistance (MDR) in cancer therapy. The discovery of ABCG2 inhibitors could assist in designing unprecedented therapeutic strategies for cancer treatment. There is as yet no approved drug targeting ABCG2, although a large number of drug candidates have been clinically investigated. In this work, binding affinities of 181 drug candidates in clinical-trial or investigational stages as ABCG2 inhibitors were inspected using in silico techniques. Based on available experimental data, the performance of AutoDock4.2.6 software was first validated to predict the inhibitor-ABCG2 binding mode and affinity. Combined molecular docking calculations and molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations, were then performed to filter out the studied drug candidates. From the estimated docking scores and MM-GBSA binding energies, six auspicious drug candidates-namely, pibrentasvir, venetoclax, ledipasvir, avatrombopag, cobicistat, and revefenacin-exhibited auspicious binding energies with value < -70.0 kcal/mol. Interestingly, pibrentasvir, venetoclax, and ledipasvir were observed to show even higher binding affinities with the ABCG2 transporter with binding energies of < -80.0 kcal/mol over long MD simulations of 100 ns. The stabilities of these three promising candidates in complex with ABCG2 transporter were demonstrated by their energetics and structural analyses throughout the 100 ns MD simulations. The current study throws new light on pibrentasvir, venetoclax, and ledipasvir as curative options for multidrug resistant cancers by inhibiting ABCG2 transporter.