Monoamine Oxidase (MAO) as a Potential Target for Anticancer Drug Design and Development.

Monoamine oxidases (MAOs) are oxidative enzymes that catalyze the conversion of biogenic amines into their corresponding aldehydes and ketones through oxidative deamination. Owing to the crucial role of MAOs in maintaining functional levels of neurotransmitters, the implications of its distorted activity have been associated with numerous neurological diseases. Recently, an unanticipated role of MAOs in tumor progression and metastasis has been reported. The chemical inhibition of MAOs might be a valuable therapeutic approach for cancer treatment. In this review, we reported computational approaches exploited in the design and development of selective MAO inhibitors accompanied by their biological activities. Additionally, we generated a pharmacophore model for MAO-A active inhibitors to identify the structural motifs to invoke an activity.

Gold Nanocomplex Strongly Modulates the PI3K/Akt Pathway and Other Pathways in MCF-7 Breast Cancer Cell Line.

Conjugating drugs with gold nanoparticles (GNP) is a key strategy in cancer therapy. Herein, the potential inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and other pathways of the MCF-7 cell-line, was investigated upon treatment with gold nanorods (GNR) conjugated with a PI3K inhibitor drug. The results revealed that the coupling of GNR with the drug drastically modulated the expression of PI3Kα at the gene and protein levels compared to the drug or GNR alone. The PI3Kα pathway is involved in tumor progression and development through the mediation of different mechanisms such as apoptosis, proliferation, and DNA damage. Treatment with the nanocomplex significantly affected the gene expression of several transcription factors responsible for cell growth and proliferation, apoptotic pathways, and cell cycle arrest. Furthermore, the gene expression of different regulatory proteins involved in cancer progression and immune responses were significantly modified upon treatment with the nanocomplex compared to the free drug or GNR alone.

N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents.

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (1H and 13C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC50 µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.

Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents.

The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC50 Caco-2 = 98 µM, IC50 HCT-116 = 337 µM) and 16 (IC50 Caco-2 = 13 µM, IC50 HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.

Hypolipidemic effect of novel 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole as potential peroxisome proliferation-activated receptor-α agonist in acute hyperlipidemic rat model.

The development of new antihyperlipidemic agents with higher potency and lower side effects is of high priority. In this study, 1,3,4 thiadiazole Schiff base derivatives were synthesized as potential peroxisome proliferation-activated receptor-α (PPARα) agonists and characterized using elemental analysis, FTIR, 1H-NMR, 13C-NMR and mass spectroscopy and then tested for their hypolipidemic activity in Triton WR-1339-induced acute hyperlipidemic rat model in comparison with bezafibrate. The compounds showed significant hypolipidemic activity. Induced fit docking showed that the compounds are potential activators of PPARα with binding scores - 8.00 Kcal/mol for 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole. PCR array analysis showed an increase in the expression of several genes involved in lipid metabolism through mitochondrial fatty acid ß oxidation and are part of PPARα signaling pathway including Acsm3, Fabp4 and Hmgcs1. Gene expression of Lrp12 and Lrp1b involved in LDL uptake by liver cells and Cyp7a1 involved in cholesterol catabolism were also found to be upregulated.

Ponicidin as a promising anticancer agent: Its biological and biopharmaceutical profile along with a molecular docking study.

Ponicidin, an ent-kaurane diterpenoid derived from Rabdosia rubescens, exhibits antitumor activities against several types of cancers. This review summarizes the botanical sources, biological activities, and biopharmaceutical profile of ponicidin. Additionally, a molecular docking study has been undertaken to correlate the interaction of this diterpenoid with biomacromolecules found in the literature. For this purpose, an up-to-date (till December 2018) literature survey was conducted using a number of databases such as PubMed, Science Direct, Web of Science, Scopus, the American Chemical Society, Clinicaltrials.gov, and Google Scholar. Findings suggest that ponicidin exerts antioxidant and anticancer activity in various test systems, including experimental animals and cultured cancer cells. Research findings revealed that anticancer mechanisms of ponicidin include antioxidant/oxidative stress induction, cytotoxic, apoptotic inductive, chemosensitizer, antiangiogenic, and antiproliferative effects. In silico study suggests that 5ITD (PI3K) was the best protein with which ponicidin interacts to exert its anticancer effect. In conclusion, ponicidin might be a promising plant-derived cancer chemotherapeutic agent.

Synthesis and in Vivo Lipid-Lowering Activity of Novel Imidazoles-5-carboxamide Derivatives in Triton-WR-1339-Induced Hyperlipidemic Wistar Rats.

A new series of imidazole-5-carboxamide derivatives were prepared and tested for their anti-hyperlipidemic activity in Triton-WR-1339-induced hyperlipidemic Wistar rats. The purpose of this research was to improve benzophenone carboxamides water solubility maintaining at the same time the antihyperlipidemic activity. Compounds 4, 6, 10, and 11 were synthesized through a coupling reaction between imidazoles-5-carbonyl chloride and amino benzophenones. The tested animals (n=48) were divided into six groups: the first group (hyperlipidemic control group; HCG) received an intraperitoneal injection (i.p.) of (300 mg/kg) Triton WR-1339. The second group received i.p. injection of Triton WR-1339 followed by an intra-gastric administration of bezafibrate (100 mg/kg) (bezafibrate; BF). The third, fourth, fifth, and sixth groups received i.p. injection of Triton WR-1339 followed by an intra-gastric administration of (30 mg/kg) of compounds 4, 6, 10, and 11, respectively. At a dose of 30 mg/kg body weight compounds 4, 6, 10, and 11 significantly (p<0.0001) decreased the plasma level of triglyceride (TG), low-density lipoprotein (LDL) and total cholesterol (TC) levels after 18 h of treatment. Additionally, compounds 4, 6, 11 and bezafibrate (100 mg/kg) significantly (p<0.0001) increased the plasma level of high-density lipoprotein (HDL) levels, which is known for its preventive role against atherogenesis. These results demonstrate the possibility of pharmacokinetic properties improvement maintaining the biological and pharmacological profile of these compounds.

Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors.

Structure-based drug design and molecular modeling were employed to identify a new series of indole-2-carboxamides as potential anticancer agents. These compounds were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectrometry as well as by elemental analysis. Molecular docking studies confirmed that the newly synthesized compounds accommodate PI3Kα and EGFR kinase catalytic sites and form H-bonding with the key binding residues. The antitumor activity of these new compounds against an array of cancer cell lines (human colon carcinoma (HCT116), leukemia (K562), and breast cancer (MDA231) was evaluated. Results revealed that these compounds were selective against the kinase domain, and none of them showed any inhibitory activity against K562. In addition, results showed that compound 13 exhibited high potency in HCT116 and MDA231 with IC50 values of 19 and 15µM, respectively. Our findings recommend that further optimization of this series would be beneficial for colon and breast cancer treatment.

Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα).

The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kα inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis.

Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

INTRODUCTION: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions. AREA COVERED: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation. EXPERT OPINION: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.

Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

INTRODUCTION: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. AREA COVERED: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. EXPERT OPINION: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

A Critical Assessment of COVID-19 Genomic Vaccines.

Vaccines are instrumental tools to fight against novel and re-emerging pathogens and curb pandemics. Vaccination has been an integral part of the multifaceted public health response to the COVID-19 pandemic. Diverse vaccine platforms have been designed and are currently at different stages of development. Some vaccines are still in early biological testing, while others have been launched after being approved by regulatory agencies worldwide. Genomic vaccines that deliver parts of the viral DNA or RNA to host cells have gained popularity recently due to their high efficiency and fast manufacture. Furthermore, recent clinical studies encouraged the use of different vaccine platforms within the primary vaccination course to enhance the efficacy of vaccination. Herein, we discuss COVID-19 genomic vaccines, which deliver viral genetic material to host cells through diverse biotechnology platforms, including viral vector vaccines, messenger RNA nucleic acid vaccines, and DNA nucleic acid vaccines. We compare and contrast vaccine characteristics, composition, and pros and cons among different genomic vaccine platforms as well as non-genomic vaccines. This review summarizes all current knowledge about COVID-19 genomic vaccines, which could be highly valuable to researchers interested in public health and vaccine development.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

Identifying a causal link between prolactin signaling pathways and COVID-19 vaccine-induced menstrual changes.

COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported menstrual cycle irregularity after receiving COVID-19 vaccines, and this led to renewed fears concerning COVID-19 vaccines and their effects on fertility. Herein we devised an informatics workflow to explore the causal drivers of menstrual cycle irregularity in response to vaccination with mRNA COVID-19 vaccine BNT162b2. Our methods relied on gene expression analysis in response to vaccination, followed by network biology analysis to derive testable hypotheses regarding the causal links between BNT162b2 and menstrual cycle irregularity. Five high-confidence transcription factors were identified as causal drivers of BNT162b2-induced menstrual irregularity, namely: IRF1, STAT1, RelA (p65 NF-kB subunit), STAT2 and IRF3. Furthermore, some biomarkers of menstrual irregularity, including TNF, IL6R, IL6ST, LIF, BIRC3, FGF2, ARHGDIB, RPS3, RHOU, MIF, were identified as topological genes and predicted as causal drivers of menstrual irregularity. Our network-based mechanism reconstruction results indicated that BNT162b2 exerted biological effects similar to those resulting from prolactin signaling. However, these effects were short-lived and didn't raise concerns about long-term infertility issues. This approach can be applied to interrogate the functional links between drugs/vaccines and other side effects.

A cross-sectional study confirms temporary post-COVID-19 vaccine menstrual irregularity and the associated physiological changes among vaccinated women in Jordan.

Background: COVID-19 vaccines continue to save people's lives around the world; however, some vaccine adverse events have been a major concern which slowed down vaccination campaigns. Anecdotal evidence pointed to the vaccine effect on menstruation but evidence from the adverse event reporting systems and the biomedical literature was lacking. This study aimed to investigate the physiological changes in women during menstruation amid the COVID-19 vaccination. Methods: A cross-sectional online survey was distributed to COVID-19 vaccinated women from Nov 2021 to Jan 2022. The results were analyzed using the SPSS software. Results: Among the 564 vaccinated women, 52% experienced significant menstrual irregularities post-vaccination compared to before regardless of the vaccine type. The kind of menstrual irregularity varied among the vaccinated women, for example, 33% had earlier menstruation, while 35% reported delayed menstruation. About 31% experienced heavier menstruation, whereas 24% had lighter menstrual flow. About 29% had menstruation last longer, but 13% had it shorter than usual. Noteworthy, the menstrual irregularities were more frequent after the second vaccine shot, and they disappeared within 3 months on average. Interestingly, 24% of the vaccinated women reported these irregularities to their gynecologist. Conclusion: The COVID-19 vaccine may cause physiological disturbances during menstruation. Luckily, these irregularities were short-termed and should not be a reason for vaccine hesitancy in women. Further studies are encouraged to unravel the COVID-19 vaccine adverse effect on women's health.

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

The alpha isoform of the phosphatidylinositol-3-kinases (PI3Kα) is often mutated, amplified and overexpressed in human tumors. In an effort to develop new inhibitors targeting this enzyme, we carried out a pharmacophore model study based on six PI3Kα-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3Kα and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3Kα, and induced apoptosis in the HCT116 colon cancer cell line. QPLD-based docking showed that residues Asp933, Glu849, Val851, and Gln859 appeared to be key binding residues for active inhibitors.

Binding selectivity studies of phosphoinositide 3-kinases using free energy calculations.

Phosphoinositide 3-kinases (PI3Ks) and their phosphatidylinositol 3,4,5-triphosphate (PIP(3)) products regulate a variety of cellular processes. Of these, PI3Kα is an attractive target for anticancer drug design. Mutations in the PI3Kα kinase domain alter the mobility of the activation loop resulting in gain of function. We employed molecular dynamics (MD) simulations-based energetic analysis using molecular mechanics/generalized born surface area (MM/GBSA) for PI3Kα and -γ. MD simulations were carried out for PI3K models based on the RESP (restrained electrostatic potential) and quantum mechanics (QM)-polarized ligand docking (QPLD)-derived partial charges. Computational alanine scanning was also used to evaluate the contributions of key binding residues to ligand binding. Our results show that both RESP and QPLD charge models of PI3Kα and PI3Kγ provide similar performance in MD simulations. For example, the predicted RESP and QPLD free energies of -9.5 and -9.3 kcal/mol for LY294002 binding to PI3Kγ and -10.9 and -11.7 kcal/mol for wortmannin binding to PI3Kα are in good agreement with experimental values. A significant loss in binding free energy was observed when hydrophobic residues were mutated to alanine, suggesting that specific hydrophobic interactions are important to optimal ligand binding. MM/GBSA calculations suggested that residues Ser774, Gln859, and Ile932 of PI3Kα might be used to design H1047R mutant-specific ligands, whereas Lys890 of PI3Kγ can be used for ligand design targeting PI3Kγ.

N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα).

This work describes our efforts to optimize the lead PI3Kα inhibitor N-benzyl 4-hydroxy-2-quinolone-3-carboxamide using structure-based design and molecular docking. We identified a series of N-phenyl 4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R versus wild-type PI3Kα and we also showed that the cell growth inhibition by these compounds likely occurs by inhibiting the formation of pAKT and induction of apoptosis.

Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects.

COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.

Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers.

The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a vast source for identifying disease biomarkers and therapeutic drug targets. Herein, we review the evidence backing the exploitation of the human microbiome for identifying diagnostic biomarkers for human disease. We describe the importance of the human microbiome in health and disease and detail the use of the human microbiome and microbiota metabolites as potential diagnostic biomarkers for multiple diseases, including cancer, as well as inflammatory, neurological, and metabolic diseases. Thus, the human microbiota has enormous potential to pave the road for a new era in biomarker research for diagnostic and therapeutic purposes. The scientific community needs to collaborate to overcome current challenges in microbiome research concerning the lack of standardization of research methods and the lack of understanding of causal relationships between microbiota and human disease.