Mutasem Omar Taha

University of Jordan | UJ · Faculty of Pharmacy

Objective: Develop a new nanomagnetic delivery system using trimetallic nanoparticles. Results: In this study, the structural morphology and the biological effects of magnetic Cu 0.5 Zn 0.5 Fe 2 O 4 nanoparticles alone and with various coatings were investigated. The nanoparticles have shown a high potential biomedical application alone and as a ta...

Introduction: Myeloproliferative neoplasms (MPNs) are rare hematopoietic disorders driven by mutations in the JAK-STAT signaling pathway genes. While JAK2 inhibitors have transformed MPN treatment, 10 they do not eliminate the malignant clone or prevent disease progression in most patients. This limitation underscores the need for more effective th...

This study revealed a new inhibitor of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), a crucial factor in cardiovascular disease and hypertension. The study focuses on the bioactivity compounds that combine adamantane/1,3,4-oxadiazole, potentially inhibiting CaMKIIδ. Various adamantyl-1,3,4-oxadiazole derivatives were synthesized and tested...

FMS-like tyrosine kinase 3 (Flt3) is an oncogenic kinase implicated in leukemia, with its primary association being acute myeloid leukemia (AML). Flt3-specific inhibitors have demonstrated promising outcomes in disrupting AML progression. While isoindigo derivatives, e.g., meisoindigo, have proven effective against chronic myeloid leukemia, their s...

This study introduces a novel class of hybrid compounds, namely, benzothieno[3,2’-f][1,3]oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines]. The synthetic strategy employs a three-component reaction and 1,4-Dipolar cycloaddition, yielding spiro and oxazepine compounds. Structural elucidation via NMR and MS analyses is comp...

Activity cliffs (ACs) are pairs of structurally similar molecules with significantly different affinities for a biotarget, posing a challenge in computer-assisted drug discovery. This study focuses on protein kinases, significant therapeutic targets, with some exhibiting ACs while others do not despite numerous inhibitors. The hypothesis that the p...

Aims: Micellar systems have the advantage of being easily prepared, cheap, and readily loadable with bioactive molecular cargo. However, their fundamental pitfall is poor stability, particularly under dilution conditions. We propose to use simple quaternary ammonium surfactants, namely, hexadecylamine (HDA) and hexadecylpyridinium (HDAP), together...

Aurora-A (AURKA) is serine/threonine protein kinase involved in the regulation of numerous processes of cell division. Numerous studies have demonstrated strong association between AURKA and cancer. AURKA is overexpressed in many cancers, such as colon, breast and prostate cancers. Consequently, AURKA has emerged as promising target for therapeutic...

A set of cyclopenten-[g]annelated isoindigos (5a-g) has been prepared and tested for their in vitro anti-proliferative activities against MCF-7 and HL60 cells. Among, the N-1-methyl-5′-nitro derivative (5g) displayed the highest activity against HL60 cells (IC 50 = 67 nM) and acted as the most potent Flt3 inhibitor. Compounds 5d-g exhibited moderat...

Due to its significant role in neurodegeneration, Cyclin‐dependent kinase 5 (CDK5) has emerged as a potential target for addressing neuropathological disorders, including Alzheimer's disease (AD). The application of CDK5 inhibitors has demonstrated promise in the treatment of AD. This prompted us to model this interesting target using a computation...

Maternal embryonic leucine zipper kinase (MELK) is a serine-threonine kinase. Several studies have revealed its role as a regulator in the tumorigenesis of various cancers. Consequently, MELK has been considered as an attractive therapeutic target for cancer management. Herein, we report pharmacophore models extracted from crystallographic complexe...

Cancer is a devastating disease, but advancements in cancer treatment offer hope for the future. Aurora kinases are a family of serine/threonine kinases that play critical roles in cell cycle control and mitosis. There are three members of the Aurora kinase family in humans: Aurora-A kinase, Aurora-B kinase, and Aurora-C kinase. This study focuses...

STAT3 belongs to a family of seven transcription factors. It plays an important role in activating the transcription of various genes involved in a variety of cellular processes. High levels of STAT3 are detected in several types of cancer. Hence, STAT3 inhibition is considered a promising therapeutic anti-cancer strategy. However, since STAT3 inhi...

Cancer is a devastating disease, but advancements in cancer treatment offer hope for the future. Aurora Kinases are a family of serine/threonine kinases that play critical roles in cell cycle control and mitosis. There are three members of the Aurora kinase family in humans: Aurora-A kinase, Aurora-B kinase, and Aurora-C kinase. This study focuses...

Background: Mechanochemistry involves the application of mechanical force to induce chemical changes in the material solid state. Mechanochemistry promises to overcome many drawbacks in pharmaceutical formulation. Chitosan (CS), a semisynthetic polymer obtained by N-deacetylation of chitin, has attracted attention in various biomedical and pharmace...

Dual specificity protein kinase threonine/Tyrosine kinase (TTK) is one of the mitotic kinases. High levels of TTK are detected in several types of cancer. Hence, TTK inhibition is considered a promising therapeutic anti-cancer strategy. In this work, we used multiple docked poses of TTK inhibitors to augment training data for machine learning QSAR...

PI3K delta signaling promotes cancer proliferation. To model this interesting target, we collected 79 PI3Kδ inhibitors of known bioactivities and divided them into four groups for pharmacophore modelling. Subsequent QSAR modelling (r²64 = 0.82, r²LOO = 0.86, F = 51.92, and r²PRESS versus 15 test inhibitors = 0.90) identified two optimal orthogonal...

GSK3b is a serine/threonine kinase that has been suggested as a putative drug target for several diseases. Recent studies have reported the beneficial effects of cephalosporin antibiotics in cancer and Alzheimer's disease, implying potential inhibition of GSK3b. To investigate this mechanism, four cephalosporins, namely, cefixime, ceftriaxone, ceph...

Aim The aim of this potential repurposing study is to investigate the potential inhibitory activity of asenapine against central nervous system CaMKII isozymes using docking experiments and enzymatic assay. Background The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase ubiquitously expressed throughout the...

STAT3 belongs to a family of seven vital transcription factors. High levels of STAT3 are detected in several types of cancer. Hence, STAT3 inhibition is considered a promising therapeutic anti-cancer strategy. In this work, we used multiple docked poses of STAT3 inhibitors to augment training data for machine learning QSAR modeling. Ligand-Receptor...

A series of novel 1,2,3-triazole-benzoxazepine hybrid molecules were synthesized and evaluated for their anticancer properties against four cancer cell lines (Caco-2, PC3, MCF-7, and HL60). Most of the synthesized compounds exhibited moderate to good cytotoxicity against tested cancer cell lines. Three of the prepared compounds, namely, 2, 3, and 4...

Lysine-specific histone demethylase 1 (LSD-1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 and is highly overexpressed in different types of cancer. Therefore, it has been widely recognized as a promising therapeutic target for cancer therapy. Towards this end, we employed various Co...

Monoglyceride lipase (MGL) is an important enzyme that plays a critical role in lipolysis and release of free fatty acids from triacylglycerides stores. High levels of circulating free fatty acids impair insulin sensitivity and induce inflammation. Several studies have shown that dipeptidyl peptidase-IV (DPP-IV) inhibitors can improve insulin sensi...

Here, we describe further cytotoxic studies and reverse pharmacophore mapping (pharmacophore profiling) for bis-triazoles MS44-53, which were designed and synthesized previously to stabilize the G-quadruplex nucleic acids capable of being formed at the telomeric region and promoter sequences of genes involved in cellular proliferation and oncogenes...

Activity cliffs (ACs) are defined as pairs of structurally similar compounds with large difference in their potencies against certain biotarget. We recently proposed that potent AC members induce significant entropically‐driven conformational modifications of the target that unveil additional binding interactions, while their weakly‐potent counterp...

Serine/threonine-protein kinase N2 (PKN2) plays an important role in cell cycle progression, cell migration, cell adhesion and transcription activation signaling processes. In cancer, however, it plays important roles in tumor cell migration, invasion and apoptosis. PKN2 inhibitors have been shown to be promising in treating cancer. This prompted u...

Cdc2-like kinase 4 (CLK4) inhibitors are of potential therapeutic value in many diseases particularly cancer. In this study, we combined extensive ligand-based pharmacophore exploration, ligand-receptor contact fingerprints generated by flexible docking, physicochemical descriptors and machine learning-quantitative structure-activity relationship (...

Background: The unprecedented global spread of coronavirus disease 2019 (COVID-19) has imposed huge challenges on the healthcare facilities, and impacted every aspect of life. This has led to the development of several vaccines against COVID-19 within one year. This study aimed to assess the attitudes and the side effects among Arab communities af...

Many missense mutations/SNPs of the TCN2 gene (which yield Transcobalamin (TC)) were reported in the literature but no study is available about their effect on binding to vitamin B12(B12) at the structural level experimentally nor computationally. Predict the effect of TC missense mutations/SNPs on binding affinity to B12 and characterize their con...

Background: Chemokines are involved in several human diseases and in different stages of COVID-19 infection and play critical role in the pathophysiology of the associated acute respiratory disease syndrome, a major complication leading to death among COVID-19 patients. In particular, CXC chemokine receptor 4 (CXCR4) was found to be highly express...

Activity cliffs (ACs) are analogous compounds of significant affinity discrepancies against certain biotarget. We propose that the ACs phenomenon is protein-related and that the propensity of certain target to have ACs can be predicted by some intrinsic protein properties. We pursued this assumption by collecting the crystallographic structures of...

Activity cliffs (ACs) are defined as closely analogous compounds of significant affinity discrepancies against certain biotarget. In this paper we propose to use AC pair(s) for extracting valid binding pharmacophores through exposing corresponding protein complexes to stochastic deformation/relaxation followed by applying genetic algorithm/machine...

Protein kinases are implicated in numerous disease conditions, and therefore, they are important therapeutic targets. In this study, Proton pump inhibitors (PPIs) were identified as potential kinase inhibitors based on their structural similarity to known inhibitors of five protein kinases, namely, CaMKIIδ, FLT3, FGFR1, ALK, and TYK2. The in vitro...

Aim: This work aims to study the effect of twoNCI compounds,NCI667916 andNCI201725 on the invasion and migration of glioblastoma U87 cells using 3Dspheroid invasion model and 2D scratch migration model. The method involves the use of two famous tumor dissemination assays including the 3D invasion spherical model and the 2D scratch model using the U...

In the present work we introduce the use of multiple docked poses for bootstrapping machine learning-based QSAR modelling. Ligand-receptor contact fingerprints are implemented as descriptor variables. We implemented this method for the discovery of potential inhibitors of the serine protease enzyme TMPRSS2 involved the infectivity of coronaviruses....

Polo-like kinase 1 (PLK1) plays vital roles in mitotic activities including G2/M transition, mitotic entry, and cytokinesis. PLK1 overexpression was observed in cancers and associated with poor prognosis. PLK1 inhibition was proven to hamper cancer hallmarks. In this research, a computational workflow named Docking-based Comparative Intermolecular...

Small interfering RNA (siRNA) has received increased interest as a gene therapeutic agent. However, instability and lack of safe, affordable, and effective carrier systems limit siRNA's widespread clinical use. To tackle this issue, synthetic vectors such as liposomes and polymeric nanoparticles have recently been extensively investigated. In this...

The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by covalent...

Protein kinases are overexpressed in various cancer cells and promote tumorigenesis. Currently, Proton Pump Inhibitors (PPIs) are investigated as anticancer agents based on their ability to counteract the acidity of the tumor microenvironment. However, the anticancer activity under physiologic pH in addition to the possession of a hydrogen bond...

Aims Design of sulfonamide-triazine derivatives as JAK1 inhibitors. Background JAK1 is a kinase involved in different autoimmune diseases. JAK1 inhibitors have shown promising results in treating autoimmune diseases. Objectives To design new JAK1 inhibitors based on sulfonamides-triazine conjugates capable of binding interactions comparable to ob...

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approva...

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) are...

Abstract: Introduction:Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. TTK targeting received recent concern for the enhancement of possible anticancer therapies. Objective: In this regard we employed our well-known method of QSAR-guided selection of best crystallographic pharmacophore(s) to discover considerable bin...

Chitosan nanoparticles (NPs) are widely studied as vehicles for drug, protein, and gene delivery. However, lack of sufficient stability, particularly under physiological conditions, render chitosan NPs of limited pharmaceutical utility. The aim of this study is to produce stable chitosan NPs suitable for drug delivery applications. Chitosan was fir...

Introduction Phosphoinositide-Dependent Kinase-1 (PDK1) is a serine/threonine kinase, which belongs to AGC kinase family required by cancer cells. Methods Pharmacophoric space of 86 PDK1 inhibitors using six diverse sets of inhibitors was explored to identify high-quality pharmacophores. The best combination of pharmacophoric models and physicoche...

Background: Currently there is overwhelming evidence linking elevated plasma free fatty acids with insulin resistance and inflammation. Monoglyceride lipase (MGL) plays crucial metabolic role in lipolysis by mediating the release of fatty acids. Therefore, inhibiting MGL should be a promising pharmacological approach for treating type 2 diabetes an...

Tyrosine Kinase 2 (TYK2) inhibition is of potential therapeutic value for treating autoimmune diseases. An elaborate ligand-based computational workflow was employed to explore structural requirements for TYK2 inhibition. Genetic function algorithm (GFA) was coupled to k-nearest neighbor (kNN) and multiple linear regression (MLR) analyses to search...

Background 3-Phosphoinositide Dependent Protein Kinase-1 (PDK1) is being lately considered as an attractive and forthcoming anticancer target. A Protein Data Bank (PDB) co-crystallized crystal provides not only rigid theoretical data but also a realistic molecular recognition data that can be explored and used to discover new hits. Objective This...

Chitosan, a natural carbohydrate polymer, has long been investigated for drug delivery and medical applications due to its biodegradability, biocompatibility and low toxicity. The micro/nanoparticulate forms of chitosan are reported to enhance the efficiency of drug delivery with better physicochemical properties including improved solubility and b...

The use of alginic acid in manufacturing of nano-particles for drug delivery.

Background: Flt3 is an oncogenic kinase involved in different leukemias. It is most prominently associated with acute myeloid leukemia (AML). Flt3-specific inhibitors have shown promising results in interfering with AML. Methods: The crystallographic structures of two inhibitors complexed within Flt3, namely, quizartinib and F6M, were used to gu...

Background: PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding. Methods: seventeen PI3Kδ crystallographic complexes were used to extract 94 pha...

Flt3 is an oncogenic kinase involved in different types of leukemia. It is most prominently associated with acute myeloid leukemia (AML). Flt3-specific inhibitors have shown promising results in interfering with AML prompting us to model this interesting target. We implemented ligand-based, QSAR-guided, pharma-cophore exploration combined with nove...