Showing papers by "Mutasem O. Taha published in 2017"

Computational modeling of the bat HKU4 coronavirus 3CLpro inhibitors as a tool for the development of antivirals against the emerging Middle East respiratory syndrome (MERS) coronavirus

Abstract: The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus that poses a major challenge to clinical management. The 3C-like protease (3CLpro) is essential for viral replication and thus represents a potential target for antiviral drug development. Presently, very few data are available on MERS-CoV 3CLpro inhibition by small molecules. We conducted extensive exploration of the pharmacophoric space of a recently identified set of peptidomimetic inhibitors of the bat HKU4-CoV 3CLpro. HKU4-CoV 3CLpro shares high sequence identity (81%) with the MERS-CoV enzyme and thus represents a potential surrogate model for anti-MERS drug discovery. We used 2 well-established methods: Quantitative structure-activity relationship (QSAR)-guided modeling and docking-based comparative intermolecular contacts analysis. The established pharmacophore models highlight structural features needed for ligand recognition and revealed important binding-pocket regions involved in 3CLpro-ligand interactions. The best models were used as 3D queries to screen the National Cancer Institute database for novel nonpeptidomimetic 3CLpro inhibitors. The identified hits were tested for HKU4-CoV and MERS-CoV 3CLpro inhibition. Two hits, which share the phenylsulfonamide fragment, showed moderate inhibitory activity against the MERS-CoV 3CLpro and represent a potential starting point for the development of novel anti-MERS agents. To the best of our knowledge, this is the first pharmacophore modeling study supported by in vitro validation on the MERS-CoV 3CLpro. Highlights MERS-CoV is an emerging virus that is closely related to the bat HKU4-CoV. 3CLpro is a potential drug target for coronavirus infection. HKU4-CoV 3CLpro is a useful surrogate model for the identification of MERS-CoV 3CLpro enzyme inhibitors. dbCICA is a very robust modeling method for hit identification. The phenylsulfonamide scaffold represents a potential starting point for MERS coronavirus 3CLpro inhibitors development.

Simulated annealing molecular dynamics and ligand–receptor contacts analysis for pharmacophore modeling

Abstract: Aim: Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand–receptor crystallographic structure can be too restricted or promiscuous. Methodology: This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand–receptor contacts analysis as means to construct pharmacophore model(s) from single ligand–receptor complex. Ligand–receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development. Results: This methodology was implemented to develop pharmacophores for acetylcholinesterase and protein kinase C-θ. The resulting models were validated by receiver-operating characteristic analysis and in vitro bioassay. Assay identified four new protein kinase C-θ inhibitors among captured hits, two of which exhibited nanomolar potencies. Conclusion: The results illustrate the ability of the new method to extract valid pharmacophores from single ligand–protein complex.

Docking-based comparative intermolecular contacts analysis and in silico screening reveal new potent acetylcholinesterase inhibitors

Abstract: The positive impact of acetylcholinesterase enzyme inhibitors on neurodegenerative diseases impelled continuous attempts to discover and optimize new acetylcholinesterase enzyme inhibitors. The combined recent interest inacetylcholinesterase enzyme inhibitors, together with known shortages of docking and docking validation methods prompted us to use our new 3D-QSAR method, namely, docking-based comparative intermolecular contacts analysis, to identify optimal docking conditions required to dock certain group of inhibitors into acetylcholinesterase enzyme binding site. Additionally, optimal docking-based comparative intermolecular contacts analysis models were converted into pharmacophore models, which were validated by receiver operating characteristic curve analysis. The pharmacophores were subsequently used as search queries to mine the national cancer institute list of compounds for new acetylcholinesterase enzyme inhibitors. Five low micromolar acetylcholinesterase enzyme inhibitors were identified. The most potent gave IC50 value of 2.55 μM.

Discovery of novel potent nuclear factor kappa‐B inhibitors (IKK‐β) via extensive ligand‐based modeling and virtual screening

Abstract: Inhibitor kappa-B kinase-beta (IKK-β) controls the activation of nuclear transcription factor kappa-B and has been linked to inflammation and cancer. Therefore, inhibitors of this kinase should have potent anti-inflammatory and anticancer properties. Accordingly, we explored the pharmacophoric space of 218 IKK-β inhibitors to identify high-quality binding models. Subsequently, genetic algorithm-based quantitative structure activity relationship (QSAR) analysis was employed to select the best possible combination of pharmacophoric models and physicochemical descriptors that explain bioactivity variation among training compounds. Three successful pharmacophores emerged in 2 optimal QSAR equations (r12175 = 0.733, r12LOO = 0.52, F1 = 65.62, r12PRESS against 43 test inhibitors = 0.63 and r22175 = 0.683, r22LOO = 0.52, F2 = 72.66, r22PRESS against 43 test inhibitors = 0.65). Two pharmacophores were merged in a single binding model. Receiver operating characteristic curve validation proved the excellent qualities of this model. The merged pharmacophore and the associated QSAR equations were applied to screen the National Cancer Institute list of compounds. Ten hits were found to exhibit potent anti-IKK-β bioactivity, out of which, one illustrates IC50 of 11.0nM.

Unsupervised pharmacophore modeling combined with QSAR analyses revealed novel low micromolar SIRT2 inhibitors.

Abstract: Situin 2 (SIRT2) enzyme is a histone deacetylase that has important role in neuronal development. SIRT2 is clinically validated target for neurodegenerative diseases and some cancers. In this study, exhaustive unsupervised pharmacophore modeling was combined with quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent SIRT2 inhibitors using 146 known SIRT2 ligands. A computational workflow that combines genetic function algorithm with k-nearest neighbor or multiple linear regression was implemented to build self-consistent and predictive QSAR models based on combinations of pharmacophores and physicochemical descriptors. Successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. Optimal QSAR models and their associated pharmacophore hypotheses were experimentally validated by identification and in vitro evaluation of several new promising SIRT2 inhibitory leads retrieved from the National Cancer Institute structural database. The most potent hit illustrated IC50 value of 5.4μM. The chemical structures of active hits were validated by proton nuclear magnetic resonance and mass spectroscopy.

Rosmarinic acid reverses the effects of metronidazole-induced infertility in male albino rats

Abstract: Rosmarinic acid (RA) is a natural antioxidant that has many biological activities. In the present study we investigated the potential of RA to reverse the negative effects of the widely used antibiotic and antiprotozoal agent metronidazole (MTZ), which is known to induce reversible male infertility. Two doses of RA (5 and 15mg kg-1) were studied in sexually mature rats with and without MTZ-induced infertility. Rats were intraperitoneally injected with 5mg kg-1 RA or 15mg kg-1 RA (in distilled water) and, 45min later, they were intraperitoneally injected with 40mg kg-1 MTZ (in distilled water). Cauda epididymidal sperm suspensions were used to assess sperm count, motility and morphology. Histological and ultrastructural studies were performed on the testes and cauda epididymidis. In rats in which infertility was not induced, neither dose of RA affected the parameters assessed. However, in sexually mature rats in which infertility was induced by 40mg kg-1 MTZ, RA at both 5 and 15mg kg-1 ameliorated the damaging effects of MTZ on final bodyweight (30 days later), sperm motility and morphology. Only 5mg kg-1 RA, and not 15mg kg-1 RA, improved the harmful effects of MTZ on the sperm count and testis ultrastructure. The findings of the present study have considerable clinical implications and suggest a possible use for RA to reverse the negative effects of MTZ on male fertility, the male reproductive system and spermatogenesis.

Discovery of Potent Bruton's Tyrosine Kinase Inhibitors Using Ligand Based Modeling.

Abstract: Background: Bruton’s Tyrosine Kinase (BTK) is a one of the Tec tyrosine kinase family. It has an essential role in B-cell development and function. Activation of BTK has been associated with the pathogenesis of many types of lymphomas and leukemia, and involved in non-life threatening autoimmune diseases. Objective: In this study, exhaustive pharmacophore modeling was combined with QSAR analyses to examine the structural requirements for anti-BTK activities. Method: Genetic function algorithm (GFA) was coupled with multiple linear regression (MLR) analysis to select the best combinations of physicochemical descriptors and pharmacophoric hypothesis capable of generating predictive and self-consistent QSAR models. The optimum pharmacophores were decorated with exclusion volumes to improve their receiver operating characteristic (ROC) curve properties. The best predictive QSAR model and its corresponding pharmacophore models were validated by discovering of novel promising BTK inhibitors retrieved from the National Cancer Institute (NCI) database. Results: Several potent hits exhibited anti-proliferative activities on U-937 cell-line in low micromolar IC50, and one active compound showed nontoxic activities on normal fibroblast cell line. Conclusion: Our efforts culminated in the identification of potent BTK ligands having desired inhibitory activities and structurally distinct from known active reference compounds (i.e., training compounds) and represent new chemotypes.

Synthesis and Structure-Activity Relationship; Exploration of some Potent Anti-Cancer Phenyl Amidrazone Derivatives.

Abstract: BACKGROUND Amidrazones have been reported to have significant anti-tumor properties against several cancer cell lines. OBJECTIVES The current project aims to profile the structure-anticancer activity relationship of phenyl-amidrazons. METHODS Fifteen phenyl-amidrazone-piperazine derivatives were prepared and tested against four cancer cell lines (leukemia, prostate, breast and colon cancers). RESULTS Six compounds illustrated low micromolar anticancer IC50 values, while the remaining compounds were either inactive or of moderate potencies. All compounds were virtually nontoxic against normal fibroblast cells. CONCLUSION Docking into the oncogenic kinase bcr/abl illustrated the critical importance of (i) phalogen substituent on the ligand's phenyl ring and (ii) the presence of positive ionizable moiety at the ligand's piperazine fragment for anticancer activity.