Belal O. Al-Najjar

Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling.

Peroxisome Proliferator-Activated Receptor γ (PPARγ) activators have drawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize new PPARγ activators. With this in mind, we explored the pharmacophoric space of PPARγ using seven diverse sets of activators. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent and predictive quantitative structure-activity relationship (QSAR) (r2(71)=0.80, F=270.3, r2LOO=0.73, r2PRESS against 17 external test inhibitors=0.67). Three orthogonal pharmacophores emerged in the QSAR equation and were validated by receiver operating characteristic (ROC) curves analysis. The models were then used to screen the national cancer institute (NCI) list of compounds. The highest-ranking hits were tested in vitro. The most potent hits illustrated EC50 values of 15 and 224 nM.

Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling

The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.

Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies

Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 μM. At 11.2 μM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.

Molecular modeling, synthesis, characterization and pharmacological evaluation of benzo[d]oxazole derivatives as non-steroidal anti-inflammatory agents

A series of N-(2-(4-chlorobenzyl)benzo[d]oxazol-5-yl)-3-substituted-propanamide (3a–3n) were synthesized and evaluated for their acute and chronic anti-inflammatory potential. The structure of the compounds was elucidated by elemental and spectral (IR, 1H NMR and MS) analysis. The synthesized compounds (at a dose of 20 mg/kg b.wt. p.o.) have shown their ability to provide 45.1–81.7% protection against carrageenan-induced paw edema, in comparison with diclofenac sodium (69.5%) and ibuprofen (64.7%). The most active compounds 3a, 3l and 3n were screened for chronic anti-inflammatory activity (cotton-pellet-induced granuloma) and to study their ulcerogenic activity. Compounds 3a, 3l and 3n showed 48.4%, 39.3% and 44.0% protection against cotton pellets-induced granuloma compared to diclofenac sodium (60.2%). The tested compounds were less ulcerogenic than the ibuprofen. Molecular modeling studies suggest that these compounds have strong interaction with the COX-2 enzyme, which is responsible for the activity.

Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients.

Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.

4-(3-Methyl­benzene­sulfonamido)­phenyl 3-methyl­benzene­sulfonate

The complete molecule of the title compound, C20H19NO5S2, is generated by a crystallographic twofold axis and the O atom and N—H group attached to the central benzene ring are statistically disordered. The dihedral angle between the central and terminal benzene rings is 56.91 (5)° and that between the terminal benzene rings is 29.80 (5)°. In the crystal, N—H⋯O hydrogen bonding links the molecules into sheets lying parallel to the ab plane.

First-Pass Metabolism Considerations in Pharmaceutical Product Development

Abstract The first-pass metabolism of a drug mainly in the gastrointestinal tract (GIT) and liver is considered as an almost unavoidable obstacle that can greatly reduce the systemic bioavailability as well as the efficacy of an orally administered drug. Therefore it is of prime importance during the process of drug development to gain proper insight and consider the various physicochemical or biochemical and physiological factors like molecular properties of drug, enzyme induction and inhibition, disease state, and others affecting the first-pass metabolism of a drug in order to design an appropriate formulation with proper excipients. This chapter mainly emphasizes the role of various physiological and biochemical factors affecting the first-pass metabolism of a drug in GIT and liver, such as of gastrointestinal motility, hepatic blood supply, plasma protein binding, genetic polymorphism, dose, and route of administration of drugs. The chapter is also contextualized with the role of prodrug development in order to circumvent the first-pass metabolism as well as to increase the bioavailability and efficacy of drugs.

Investigation of 15-hydroxyprostaglandin dehydrogenase catalytic reaction mechanism by molecular dynamics simulations

15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a prostaglandin metabolizing enzyme that oxidizes the hydroxyl group at carbon 15 (C15). The aim of the present work is to propose the main amino acids that catalyze the reaction through studying the intermolecular interaction between the ligand and the enzyme inside the active site using molecular dynamics simulation (MD). Therefore, MD simulations for two 15-PGDH systems bound with a substrate (PGE2) or an inhibitor (compound 4) were performed to investigate the importance of ligand interaction on the behavior of amino acids in the active site. Findings from this work proposed the amino acids: Tyr151, Gln148 & Asn95 to act as a catalytic triad for the reaction as hydrogen bond interactions, dihedral rotation analysis and MM-GBSA free energy calculations revealed.

4-(4-Fluoro­benzene­sulfonamido)­phenyl 4-fluoro­benzene­sulfonate

In the title compound, C18H13F2NO5S2, the complete molecule is generated by a crystallographic inversion centre, and the O atom and the N—H group attached to the central ring are statistically disordered. The dihedral angle between the central and terminal benzene rings is 64.03 (6)°. In the crystal, N—H⋯O, C—H⋯F and C—H⋯O interactions link the molecules into a three-dimensional network.