Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents.

Sixteen novel 2-aminobenzothiazole compounds with different amines or substituted piperazine moieties were designed, synthesized, and tested using various methods. Potential interactions were assessed by docking new compounds in the adenosine triphosphate (ATP) binding domain of the PI3Kγ enzyme (PDB code: 7JWE) by nucleophilic substitution or solvent-free/neat fusion for docked compound synthesis. Final 2-aminobenzothiazole compounds were characterized by direct probe gas chromatography-mass spectrometry (GC-MS), proton (H-NMR), carbon-13 (C-NMR), and attenuated total reflectance-infrared Fourier transform infrared (ATR FT-IR).

Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

Background: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL.

Evaluation of Ferulic Acid Based Multifunctional Conjugates as Potential Drug Candidates.

Background: Recent research has shown that ferulic acid (FA, trans-4-hydroxy-3- methoxycinnamic acid) has remarkable antioxidant properties and a wide range of biological activities. Conjugation of two or more biologically active compounds to produce a novel molecular scaffold is justified by the need to enhance biological activity against a single target or obtain a conjugate that behaves as a multi-target-directed ligand. In addition, the conjugation strategy decreases dose-dependent side effects by promoting the use of smaller doses of conjugated components to treat the disease.

Novel Sulfonamide-Triazine Hybrid Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents.

The biological benefits of trisubstituted 1,3,5-triazine derivatives include their ability to reduce inflammation and fight cancer. A unique series of sulfonamide-triazine hybrid molecules were produced chemically by synthesizing triazine derivatives utilizing the usual nucleophilic aromatic substitution of cyanuric chloride via the solvent-free/neat fusion method. Fourier-transform infrared spectroscopy (FTIR), H NMR, and C NMR spectroscopic analyses were used to identify novel trisubstituted synthetic compounds.

Pharmacophore Modeling of Targets Infested with Activity Cliffs via Molecular Dynamics Simulation Coupled with QSAR and Comparison with other Pharmacophore Generation Methods: KDR as Case Study.

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 counterparts are enthalpically-driven binders with little influence on the protein target. We herein propose to extract pharmacophores for ACs-infested target(s) from molecular dynamics (MD) frames of purely "enthalpic" potent binder(s) complexed within the particular target.

Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores.

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.

Identification of the First "Two Digit Nano-molar" Inhibitors of the Human Glyoxalase-I Enzyme as Potential Anticancer Agents.

Background: Glyoxalase-I (Glo-I) enzyme is recognized as an indispensable druggable target in cancer treatment. Its inhibition will lead to the accumulation of toxic aldehyde metabolites and cell death. Paramount efforts were spent to discover potential competitive inhibitors with the aim to eradicate cancer.

Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In Vitro Assay.

Introduction: Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. Recently, TTK targeting came into focus for the enhancement of possible anticancer therapies.

Objective: In this regard, we employed our well-known method of QSAR-guided selection of the best crystallographic pharmacophore(s) to discover considerable binding interactions that transfer inhibitors into TTK1 binding site.

Combined High Throughput Screening with QSAR Analysis Unravelling Potential Glyoxalase-I Inhibitors.

Aims: Discovery of new Glo-I inhibitors as potential anticancer agents.

Background: Glyoxalase system is ubiquitous system in human cells which has been examined thoroughly for its role in cancerous diseases. It performs detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic bystanders.

Ligand Based Pharmacophore Modeling Followed by Biological Screening Lead to Discovery of Novel PDK1 Inhibitors as Anticancer Agents.

Background: 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 physicochemical descriptors was selected by genetic algorithm-based QSAR analysis that can elucidate the variation of bioactivity within the training inhibitors.

Investigation of Binding Characteristics of Phosphoinositide-dependent Kinase-1 (PDK1) Co-crystallized Ligands Through Virtual Pharmacophore Modeling Leading to Novel Anti-PDK1 Hits.

Background: 3-Phosphoinositide Dependent Protein Kinase-1 (PDK1) is being lately considered as an attractive and forthcoming anticancer target. A Protein Data Bank (PDB) cocrystallized 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 incited us to investigate the co-crystallized ligands' contacts inside the PDK1 binding pocket via a structure-based receptor-ligand pharmacophore generation technique in Discovery Studio 4.

Combination of pharmacophore modeling and 3D-QSAR analysis of potential glyoxalase-I inhibitors as anticancer agents.

Glyoxalase system is an ubiquitous system in human cells which has been examined thoroughly for its role in different diseases. It comprises two enzymes; Glyoxalase I (Glo-I) and Glyoxalase II (Glo-II) which perform detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic bystanders. In silico computer Aided Drug Design approaches were used and ninety two diverse pharmacophore models were generated from eighteen Glyoxalase I crystallographic complexes.

Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis.

Background: PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding.

Ligand-based modeling of Akt3 lead to potent dual Akt1/Akt3 inhibitor.

Akt1 and Akt3 are important serine/threonine-specific protein kinases involved in G2 phase required by cancer cells to maintain cell cycle and to prevent cell death. Accordingly, inhibitors of these kinases should have potent anti-cancer properties. This prompted us to use pharmacophore/QSAR modeling to identify optimal binding models and physicochemical descriptors that explain bioactivity variation within a set of 74 diverse Akt3 inhibitors.

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

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.

Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation.

The pharmacophoric features of the virtual cocrystallized protein of 178 Hsp90 proteins were obtained from the protein data bank and explored to generate 1260 pharmacophores evaluated using the decoy list composed of 1022 compounds. Accordingly, 51 pharmacophores were selected with high receiver operating characteristic (ROC) value for further processing. 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 a self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (R = 0.

Evaluation of novel Akt1 inhibitors as anticancer agents using virtual co-crystallized pharmacophore generation.

The pharmacophoric features of the virtual co-crystallized protein of 17 Akt1 proteins were downloaded from the protein data bank, and explored to end up with 132 generated pharmacophores that had been evaluated using the decoy list composed of 1724 compounds. The areas under the curve of the Receiver-Operating Characteristic (ROC-AUC) were sorted, and the highest ranked pharmacophore 3MV5_2_01 was selected to be used as a searching tool in the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best fitted compounds were selected.

Discovery of nanomolar phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.

Phosphoinositide 3-kinase gamma (PI3Kγ) is member of a family of enzymes involved in cancer pathogenesis. Accordingly, considerable efforts have been carried out to develop new PI3Kγ inhibitors. Towards this end we explored the pharmacophoric space of PI3Kγ using three diverse sets of inhibitors.

Discovery of novel urokinase plasminogen activator (uPA) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.

Urokinase plasminogen activator (uPA)-a serine protease-is thought to play a central role in tumor metastasis and angiogenesis and, therefore, inhibition of this enzyme could be beneficial in treating cancer. Toward this end, we explored the pharmacophoric space of 202 uPA inhibitors using seven diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, we employed genetic algorithm-based quantitative structure-activity relationship (QSAR) analysis as a competition arena to select the best possible combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within the training inhibitors (r (2) 162 = 0.

Elaborate ligand-based modeling reveal new migration inhibitory factor inhibitors.

Recent research suggested the involvement of migration inhibitor factor (MIF) in cancer and inflammatory diseases, which prompted several attempts to develop new MIF inhibitors. Accordingly, we investigated the pharmacophoric space of 79 MIF inhibitors using seven diverse subsets of inhibitors to identify plausible binding hypotheses (pharmacophores). Subsequently, we implemented genetic algorithm and multiple linear regression analysis to select optimal combination of pharmacophores and physicochemical descriptors capable of explaining bioactivity variation within the training compounds (QSAR model, r63=0.

Application of docking-based comparative intermolecular contacts analysis to validate Hsp90α docking studies and subsequent in silico screening for inhibitors.

Heat shock protein (Hsp90α) has been recently implicated in cancer, prompting several attempts to discover and optimize new Hsp90α inhibitors. Towards this end, we docked 83 diverse Hsp90α inhibitors into the ATP-binding site of this chaperone using several docking-scoring settings. Subsequently, we applied our newly developed computational tool--docking-based comparative intramolecular contacts analysis (dbCICA)--to assess the different docking conditions and select the best settings.

Some sulfonamide drugs inhibit ATPase activity of heat shock protein 90: investigation by docking simulation and experimental validation.

Eight selected sulfonamide drugs were investigated as inhibitors of heat shock protein 90 (Hsp90). The investigation included simulated docking experiments to fit the selected compounds within the binding pocket of Hsp90. The selected molecules were found to readily fit within the ATP-binding pocket of Hsp90 in low-energy poses.

Elaborate ligand-based modeling reveals new nanomolar heat shock protein 90α inhibitors.

Heat shock protein (Hsp90α) has been recently implicated in cancer prompting several attempts to discover and optimize new Hsp90α inhibitors. Toward this end, we explored the pharmacophoric space of 83 Hsp90α inhibitors using six diverse sets of inhibitors to identify high-quality pharmacophores. 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 a self-consistent quantitative structure activity relationship (QSAR) of optimal predictive potential (r(67)(2)=0.

Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay.

Cyclin-dependent kinase 1 (CDK1) is a valid anticancer target. With this in mind we applied a modeling workflow by combining pharmacophore modeling and QSAR analysis followed by in silico screening towards the discovery of novel inhibitory CDK1 scaffolds. Virtual screening identified 10 low micromolar inhibitory leads: 8 from the National Caner Institute (NCI) list of compounds and 2 from our in house list of established drugs and agrochemicals.