New Theobromine Apoptotic Analogue with Anticancer Potential Targeting the EGFR Protein: Computational and In Vitro Studies.

AIM: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of existing EGFR inhibitors as a foundation. METHOD: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA. Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA's binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA. Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations. RESULTS: DFT studies indicated T-1-PMPA's reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA's safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFRWT and EGFR790m, with IC50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC50 values of 3.51 and 4.13 µM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA. Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib's values (84 and 74%), respectively. CONCLUSION: In conclusion, our study's findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR.

Dapoxetine versus glans penis injection with hyaluronic acid gel in treatment of premature ejaculation.

Objective: to compare the results of using Dapoxetine and HA (hyaluronic acid) gel injection by Five puncture technique in the treatment of premature ejaculation (PE). Methods: 100 sexually active heterosexuals circumcised males with lifelong PE were included in the study. Group A patients were treated with on-demand Dapoxetine, while group B was treated with HA gel glans penis injection using a five-puncture technique. Both groups were evaluated at 1st,3rd and 6th months post-treatment using IELT. Results: There were no significant differences between both groups regarding patient demographic. Mean pretreatment IELT in groups A and B were 45.82 ± 7.44 and 46.18 ± 7.82 receptively. There was no significant difference between both groups. After treatment, both groups show significant ILET improvement during the 1st,3rd, and 6th months follow-up with a P value < 0.001. However, when comparing the improvement of ILET in group A (Dapoxetine) and group B (HA injection), there were high significance differences in favor of group B in the 1st,3rd, and 6th-month follow-up. Conclusion: Although both treatment modalities have improved IELT and premature ejaculation, but HA injection with five punctures technique was significantly better than oral Dapoxetine with self-limited side effects.

New thiazolidine-2,4-diones as potential anticancer agents and apoptotic inducers targeting VEGFR-2 kinase: Design, synthesis, in silico and in vitro studies.

BACKGROUND: VEGFR-2 has emerged as a prominent positive regulator of cancer progression. AIM: Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. METHODS: Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed. RESULTS: Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC50 value of 0.066 µM. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC50 values ranging from 0.04 to 4.71 µM, relative to sorafenib (IC50 = 2.24 ± 0.06 and 3.17 ± 0.01 µM against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2. CONCLUSION: Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer.

Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC-MS/MS cancer cell entrapment assays.

Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.

In silico and in vitro evaluation of the anti-virulence potential of patuletin, a natural methoxy flavone, against Pseudomonas aeruginosa.

This study aimed to investigate the potential of patuletin, a rare natural flavonoid, as a virulence and LasR inhibitor against Pseudomonas aeruginosa. Various computational studies were utilized to explore the binding of Patuletin and LasR at a molecular level. Molecular docking revealed that Patuletin strongly interacted with the active pocket of LasR, with a high binding affinity value of -20.96 kcal/mol. Further molecular dynamics simulations, molecular mechanics generalized Born surface area (MM/GBSA), protein-ligand interaction profile (PLIP), and essential dynamics analyses confirmed the stability of the patuletin-LasR complex, and no significant structural changes were observed in the LasR protein upon binding. Key amino acids involved in binding were identified, along with a free energy value of -26.9 kcal/mol. In vitro assays were performed to assess patuletin's effects on P. aeruginosa. At a sub-inhibitory concentration (1/4 MIC), patuletin significantly reduced biofilm formation by 48% and 42%, decreased pyocyanin production by 24% and 14%, and decreased proteolytic activities by 42% and 20% in P. aeruginosa isolate ATCC 27853 (PA27853) and P. aeruginosa clinical isolate (PA1), respectively. In summary, this study demonstrated that patuletin effectively inhibited LasR activity in silico and attenuated virulence factors in vitro, including biofilm formation, pyocyanin production, and proteolytic activity. These findings suggest that patuletin holds promise as a potential therapeutic agent in combination with antibiotics to combat antibiotic-tolerant P. aeruginosa infections.

Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies.

In this study, a series of seven novel 2,4-dioxothiazolidine derivatives with potential anticancer and VEGFR-2 inhibiting abilities were designed and synthesized as VEGFR-2 inhibitors. The synthesized compounds were tested in vitro for their potential to inhibit VEGFR-2 and the growth of HepG2 and MCF-7 cancer cell lines. Among the compounds tested, compound 22 (IC50 = 0.079 µM) demonstrated the highest anti-VEGFR-2 efficacy. Furthermore, it demonstrated significant anti-proliferative activities against HepG2 (IC50 = 2.04 ± 0.06 µM) and MCF-7 (IC50 = 1.21 ± 0.04 M). Additionally, compound 22 also increased the total apoptotic rate of the MCF-7 cancer cell lines with cell cycle arrest at S phase. As well, computational methods were applied to study the VEGFR-2-22 complex at the molecular level. Molecular docking and molecular dynamics (MD) simulations were used to investigate the complex's structural and kinetic characteristics. The DFT calculations further revealed the structural and electronic properties of compound 22. Finally, computational ADMET and toxicity tests were performed indicating the likeness of the proposed compounds to be drugs. The results suggest that compound 22 displays promise as an effective anticancer treatment and can serve as a model for future structural modifications and biological investigations in this field.

Anti-virulence potential of patuletin, a natural flavone, against Staphylococcus aureus: In vitro and In silico investigations.

Staphylococcus aureus is a highly prevalent and aggressive human pathogen causing a wide range of infections. This study aimed to explore the potential of Patuletin, a rare natural flavone, as an anti-virulence agent against S. aureus. At a sub-inhibitory concentration (1/4 MIC), Patuletin notably reduced biofilm formation by 27 % and 23 %, and decreased staphyloxanthin production by 53 % and 46 % in Staphylococcus aureus isolate SA25923 and clinical isolate SA1, respectively. In order to gain a more comprehensive understanding of the in vitro findings, several in silico analyses were conducted. Initially, a 3D-flexible alignment study demonstrated a favorable structural similarity between Patuletin and B70, the co-crystallized ligand of CrtM, an enzyme that plays a pivotal role in the biosynthesis of staphyloxanthin. Molecular docking highlighted the strong binding of Patuletin to the active site of CrtM, with a high affinity of -20.95 kcal/mol. Subsequent 200 ns molecular dynamics simulations, along with MM-GBSA, ProLIF, PLIP, and PCAT analyses, affirmed the stability of the Patuletin-CrtM complex, revealing no significant changes in CrtM's structure upon binding. Key amino acids crucial for binding were also identified. Collectively, this study showcased the effective inhibition of CrtM activity by Patuletin in silico and its attenuation of key virulence factors in vitro, including biofilm formation and staphyloxanthin production. These findings hint at Patuletin's potential as a valuable therapeutic agent, especially in combination with antibiotics, to counter antibiotic-resistant Staphylococcus aureus infections.

Structure of the O-polysaccharide from the moderately halophilic bacterium Halomonas fontilapidosi KR26.

Lipopolysaccharide was obtained from the aerobic moderately halophilic bacterium Halomonas fontilapidosi KR26. The O-polysaccharide was isolated by mild acid degradation of the lipopolysaccharide and was examined by chemical methods and by 1H and 13C NMR spectroscopy, including 1H,1H COSY, TOCSY, ROESY, and 1H,13C HSQC, and HMBC experiments. The following structure of the linear tetrasaccharide repeating unit was deduced. →2)-α-l-Rhap-(1→2)-α-l-Rhap-(1→3)-α-l-Rhap-(1→3)-ß-d-Galp-(1→.

QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors.

This study presents a robust and integrated methodology that harnesses a range of computational techniques to facilitate the design and prediction of new inhibitors targeting the JAK3/STAT pathway. This methodology encompasses several strategies, including QSAR analysis, pharmacophore modeling, ADMET prediction, covalent docking, molecular dynamics (MD) simulations, and the calculation of binding free energies (MM/GBSA). An efficacious QSAR model was meticulously crafted through the employment of multiple linear regression (MLR). The initial MLR model underwent further refinement employing an artificial neural network (ANN) methodology aimed at minimizing predictive errors. Notably, both MLR and ANN exhibited commendable performance, showcasing R2 values of 0.89 and 0.95, respectively. The model's precision was assessed via leave-one-out cross-validation (CV) yielding a Q2 value of 0.65, supplemented by rigorous Y-randomization. , The pharmacophore model effectively differentiated between active and inactive drugs, identifying potential JAK3 inhibitors, and demonstrated validity with an ROC value of 0.86. The newly discovered and designed inhibitors exhibited high inhibitory potency, ranging from 6 to 8, as accurately predicted by the QSAR models. Comparative analysis with FDA-approved Tofacitinib revealed that the new compounds exhibited promising ADMET properties and strong covalent docking (CovDock) interactions. The stability of the new discovered and designed inhibitors within the JAK3 binding site was confirmed through 500 ns MD simulations, while MM/GBSA calculations supported their binding affinity. Additionally, a retrosynthetic study was conducted to facilitate the synthesis of these potential JAK3/STAT inhibitors. The overall integrated approach demonstrates the feasibility of designing novel JAK3/STAT inhibitors with robust efficacy and excellent ADMET characteristics that surpass Tofacitinib by a significant margin.Communicated by Ramaswamy H. Sarma.

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer.

The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA's total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA's correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.

New nicotinamide derivatives as potential anticancer agents targeting VEGFR-2: design, synthesis, in vitro, and in silico studies.

Herin, new nicotinamide candidates were designed and synthesized as VEGFR-2 inhibitors. In vitro antiproliferative activities were assessed against MCF-7, HepG-2 and HCT-116 cancer cell lines. The top cytotoxic members 15a, 15b, 16, 18a, and 18b were estimated against their selected target (VEGFR-2). Further mechanistic tests were studied for the most potent cytotoxic candidate 18a, these studies revealed the ability of compound 18a to hinder the progression of HCT-116 cells at S and Pre-G1phases besides boosting early and late apoptosis. Also compound 18a was found to significantly decrease the levels immunomodulatory proteins TNF-α and IL-6 while showing a four-fold rise in an apoptotic marker caspase-3 when compared to control cells. The therapeutic index of the designed derivatives was evaluated by computational ADMET and toxicity calculations as well as their potentiality to occupy the VEGFR-2 active site was signposted by molecular docking assessments. Finally, molecular dynamic simulation studies of compound 18a-VEGFR-2 complex indicated the high steadiness of compound 18a in the VEGFR-2 active site. This study presents compound 18a as a lead candidate that can be optimized to get a strong VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.

Rationale design and synthesis of new apoptotic thiadiazole derivatives targeting VEGFR-2: computational and in vitro studies.

This work presents the synthesis and in vitro, and in silico analyses of new thiadiazole derivatives that are designed to mimic the pharmacophoric characteristics of vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. A comprehensive evaluation of the inhibitory properties of the synthesized thiadiazole derivatives against the cancer cell lines MCF-7 and HepG2 identified several auspicious candidates. Among them, compound 14 showed remarkably low IC50 values of 0.04 µM and 0.18 µM against MCF-7 and HepG2, respectively. VEGFR-2 inhibitory evaluation of compound 14 revealed a promising IC50 value in the nanomolar range (103 nM). Further examination of the cell cycle revealed that compound 14 has the ability to stop the progression of the cell cycle in MCF-7 cells via G0-G1 phase arrest. Interestingly, compound 14 also demonstrated a noteworthy pro-apoptotic effect in MCF-7 cells, with notable increases in early apoptosis (16.53%) and late apoptosis (29.57%), along with a slight increase in the population of necrotic cells (5.95%). Furthermore, compound 14 showed a significant drop in MCF-7 cells' ability to migrate and heal wounds. Additionally, compound 14 promoted apoptosis by boosting BAX (6-fold) while lowering Bcl-2 (6.2-fold). The binding affinities of the synthesized candidates to their target (VEGFR-2) were confirmed by computational investigations, including molecular docking, principal component analysis of trajectories (PCAT), and molecular dynamics (MD) simulations. Additionally, compound 14's stability and reactivity were investigated using density functional theory (DFT). These thorough results highlight compound 14's potential as a lead contender for additional research in the creation of anticancer drugs that target VEGFR-2. This work establishes a foundation for promising thiadiazole derivatives for future therapeutic developments in anticancer- and angiogenesis-related scientific fields.

Biological Synthesis, Characterization, and Therapeutic Potential of S. commune-Mediated Gold Nanoparticles.

Green-synthesized gold nanoparticles demonstrate several therapeutic benefits due to their safety, non-toxicity, accessibility, and ecological acceptance. In our study, gold nanoparticles (AuNPs) were created using an extracellular extract from the fungus Schizophyllum commune (S. commune). The reaction color was observed to be a reddish pink after a 24 h reaction, demonstrating the synthesis of the nanoparticles. The myco-produced nanoparticles were investigated using transmission electron microscopy (TEM), dynamic light scattering (DLS), and UV-visible spectroscopy. The TEM pictures depicted sphere-like shapes with sizes ranging from 60 and 120 nm, with an average diameter of 90 nm, which is in agreement with the DLS results. Furthermore, the efficiency of the AuNPs' antifungal and cytotoxic properties, as well as their production of intracellular ROS, was evaluated. Our findings showed that the AuNPs have strong antifungal effects against Trichoderma sp. and Aspergillus flavus at increasing doses. Additionally, the AuNPs established a dose-dependent activity against human alveolar basal epithelial cells with adenocarcinoma (A549), demonstrating the potency of synthesized AuNPs as a cytotoxic agent. After 4 h of incubation with AuNPs, a significant increase in intracellular ROS was observed in cancer cells. Therefore, these metallic AuNPs produced by fungus (S. commune) can be used as an effective antifungal, anticancer, and non-toxic immunomodulatory delivery agent.

Novel sofosbuvir derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective.

The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and human health, and the emerging resistant variants are an ongoing threat. One essential protein to target to prevent virus replication is the viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, a uridine nucleotide analog that potently inhibits viral polymerase, has been found to help treat SARS-CoV-2 patients. This work combines molecular docking and dynamics simulation (MDS) to test 14 sofosbuvir-based modifications against SARS-CoV-2 RdRp. The results reveal comparable (slightly better) average binding affinity of five modifications (compounds 3, 4, 11, 12, and 14) to the parent molecule, sofosbuvir. Compounds 3 and 4 show the best average binding affinities against SARS-CoV-2 RdRp (- 16.28 ± 5.69 and - 16.25 ± 5.78 kcal/mol average binding energy compared to - 16.20 ± 6.35 kcal/mol for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. The present study proposes compounds 3 and 4 as potential SARS-CoV-2 RdRp blockers, although this has yet to be proven experimentally.

Discovery of new VEGFR-2 inhibitors and apoptosis inducer-based thieno[2,3-d]pyrimidine.

Background: VEGFR-2 is a key regulator of cancer cell proliferation, migration and angiogenesis. Aim: Development of thieno[2,3-d]pyrimidine derivatives as potential anti-cancer agents targeting VEGFR-2. Methods: Seven in vitro and nine in silico studies were conducted. Results: Compound 10d demonstrated strong anticancer potential, boosting apoptosis based on VEGFR-2 inhibition. It arrested the S phase of the cell cycle and upregulated the apoptotic factors. Docking and molecular dynamics simulation studies confirm the stability of the VEGFR-2-10d complex and suggest that these compounds have good binding affinities to VEGFR-2. In addition, the drug-likeness was confirmed. Conclusion: Thieno[2,3-d]pyrimidines, particularly compound 10d, has good anticancer effects and may contribute to the development of new anticancer therapies.

Exploring the anticancer properties of a new nicotinamide analogue: Investigations into in silico analysis, antiproliferative effects, selectivity, VEGFR-2 inhibition, apoptosis induction, and migration suppression.

BACKGROUND: This study focuses on the development and evaluation of (E)-N-(3-(1-(2-(4-bromobenzoyl)hydrazono)ethyl)phenyl)nicotinamide (BHEPN) as a potential inhibitor of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2). METHODS: Computational investigations as density function theory (DFT), docking, molecular dynamics (MD) simulations, and ADMET) in addition to in vitro (VEGFR-2 inhibition, cytotoxicity against HepG2 and MCF-7 cancer cell lines, selectivity index, cells cycle analysis, apoptosis investigation, and cells migration assay) studies were conducted. RESULTS: DFT calculations determined the three-dimensional structure and indicated the reactivity of BHEPN. Molecular docking, and MD simulations analysis showed the BHEPN's binding affinity and its potential as a VEGFR-2 inhibitor. ADMET assessments predicted BHEPN's safety and drug-like characteristics. In vitro investigations confirmed the inhibition of VEGFR-2 with an IC50 value of 0.320 ± 0.012 µM. BHEPN also exhibited remarkable cytotoxic effects against HepG2 and MCF-7 cancer cell lines, with IC50 values of 0.19 ± 0.01 µM and 1.18 ± 0.01 µM, respectively, outperforming Sorafenib's IC50 values (2.24 ± 0.06 µM and 3.17 ± 0.01 µM), respectively. Notably, BHEPN displayed a higher IC50 value of 4.11 ± 0 µM against the non-carcinogenic Vero cell lines, indicating selectivity index values of 21.6 and 3.4 against the tested cancer cell lines, respectively. In a flow cytometry assay, BHEPN induced HepG2 cell cycle arrest at the G1/S phase. Moreover, BHEPN increased the incidence of early and late apoptosis in HepG2 cell lines (from 1.38% and 0.22%) in control cells to (4.11-26.02%) in the treated cells, respectively. Additionally, the percentage of necrosis raised to 13.39%, in contrast to 0.62% in control cells. Finally, BHEPN was able to reduce the migration and wound healing abilities in HepG2 cells to 38.89% compared to 87.92% in untreated cells after 48 h. These in vitro results aligned with the computational predictions, providing strong evidence of BHEPN's efficacy and safety in anticancer applications. CONCLUSIONS: BHEPN is a promising candidate for the development of novel anticancer agents through further in vitro and in vivo investigations.

Computer-assisted drug discovery (CADD) of an anti-cancer derivative of the theobromine alkaloid inhibiting VEGFR-2.

VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA's oral treatment didn't show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.

Design, Molecular Modeling, MD Simulations, Essential Dynamics, ADMET, DFT, Synthesis, Anti-proliferative, and Apoptotic Evaluations of a New Anti-VEGFR-2 Nicotinamide Analogue.

OBJECTIVES: This study aims to design and evaluate (in silico and in vitro) a new nicotinamide derivative as an inhibitor of VEGFR-2, a major mediator of angiogenesis Methods: The following in silico studies were performed; DFT calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, and PCAT studies. The compound's in silico (ADMET) analysis was also conducted. Subsequently, the compound ((E)-N-(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) was successfully synthesized and designated as compound X. In vitro, VEGFR-2 inhibition and cytotoxicity of compound X against HCT-116 and A549 cancer cell lines and normal Vero cell lines were conducted. Apoptosis induction and migration assay of HCT-116 cell lines after treatment with compound X were also evaluated. RESULTS: DFT calculations assigned stability and reactivity of compound X. Molecular docking and MD simulations indicated its excellent binding against VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, and PCAT studies confirmed compound X's correct binding with optimal dynamics and energy. ADMET analysis expressed its general likeness and safety. The in vitro assays demonstrated that compound X effectively inhibited VEGFR-2, with an IC50 value of 0.319 ± 0.013 µM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC50 values of 57.93 and 78.82 µM, respectively. Importantly, compound X exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC50 = 164.12 µM). Additionally, compound X significantly induced apoptosis of HCT-116 cell lines and inhibited their potential to migrate and heal. CONCLUSION: In summary, the presented study has identified compound X as a promising candidate for the development of a novel apoptotic lead anticancer drug.

In silico computational drug discovery: a Monte Carlo approach for developing a novel JAK3 inhibitors.

Inhibition of Janus kinase 3 (JAK3), a member of the JAK family of tyrosine kinases, remains an essential area of research for developing treatments for autoimmune diseases, particularly cancer and rheumatoid arthritis. The recent discovery of a new JAK3 protein, PDB ID: 4Z16, offers exciting possibilities for developing inhibitors capable of forming a covalent bond with the Cys909 residue, thereby contributing to JAK3 inhibition. A powerful prediction model was constructed and validated using Monte Carlo methods, employing various internal and external techniques. This approach resulted in the prediction of eleven new molecules, which were subsequently filtered to identify six compounds exhibiting potent pIC50 values. These candidates were then subjected to ADMET analysis, molecular docking (including reversible-reversible docking with tofacitinib, an FDA-approved drug, and reversible-irreversible docking for the newly designed compounds), molecular dynamics (MD) analysis for 300 ns, and calculation of free binding energy. The results suggested that these compounds hold promise as JAK3 inhibitors. In summary, the new compounds have exhibited favorable outcomes compared to other compounds across various modeling approaches. The collective findings from these investigations provide valuable insights into the potential therapeutic applications of covalent JAK3 inhibitors, offering a promising direction for the development of novel treatments for autoimmune disorders.Communicated by Ramaswamy H. Sarma.

Anti-breast cancer potential of a new xanthine derivative: In silico, antiproliferative, selectivity, VEGFR-2 inhibition, apoptosis induction and migration inhibition studies.

BACKGROUND: The overexpression of VEGFR-2 receptors in breast cancer provides a valuable approach to anticancer strategies. Targeting VEGFR-2, a new semisynthetic compound (T-1-MCPAB) has been designed. METHODS: Computational methods (ADMET, toxicity, DFT, Molecular Docking, Molecular Dynamics Simulations, MM-GBSA, PLIP, and PCAT) were conducted. In addition to the semi-synthesis, in vitro studies (anti-VEGFR-2, anti-proliferative, flow cytometry, and wound scratch assay) were employed. RESULTS: ADME and toxicity profiles of T-1-MCPAB studies indicated its overall drug-likeness showing results much better than Sorafenib. Then, T-1-MCPAB's exact 3D structure, stability, and reactivity were evoked by the DFT calculations. Molecular docking, molecular dynamics simulations, MM-GPSA, PLIP, and PCAT studies denoted the correct binding and inhibiting potential of T-1-MCPAB, towards VEGFR-2 protein. After the semisynthesis, T-1-MCPAB inhibited VEGFR-2 with an IC50 of 0.135 µM, which was comparable to sorafenib's IC50 of 0.0591 µM. T-1-MCPAB also showed a notable performance against MCF7 and T47D breast cancer cell lines with IC50 values of 30.95 µM and 63.64 µM, respectively, and had high selectivity index values of 3.7 and 1.8, respectively. Furthermore, T-1-MCPAB influenced early and late apoptosis and significantly decreased the potential of MCF7 cells to heal and migrate. CONCLUSION: T-1-MCPAB is a promising VEGFR-2 inhibitor with potential for breast cancer treatment. Further chemical and biological studies are needed to explore its potential as a therapeutic agent.