Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors

Tryptophan hydroxylase-1 (TPH1) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. In this study, a combination of ligand-based and structure-based methods is used to clarify the essential quantitative structure-activity relationship (QSAR) of known TPH1 inhibitors. A multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of TPH1 kinase based on three crystal structures of TPH1-inhibitor complex. This model has been successfully used to identify the bioactive conformation and align 32 structurally diverse substituted phenylalanine derivatives. The QSAR analyses have been performed on these TPH1 inhibitors based on the MCBP guided alignment. These results may provide important information for further design and virtual screening of novel TPH1 inhibitors

Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) Studies on α1A-Adrenergic Receptor Antagonists Based on Pharmacophore Molecular Alignment

The α1A-adrenergic receptor (α1A-AR) antagonist is useful in treating benign prostatic hyperplasia, lower urinary tract symptoms, and cardiac arrhythmia. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on a set of α1A-AR antagonists of N-aryl and N-nitrogen class. Statistically significant models constructed from comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established based on a training set of 32 ligands using pharmacophore-based molecular alignment. The leave-oneout cross-validation correlation coefficients were q2 CoMFA = 0.840 and q2 CoMSIA = 0.840. The high correlation between the cross-validated/predicted and experimental activities of a test set of 12 ligands revealed that the CoMFA and CoMSIA models were robust (r2 pred/CoMFA = 0.694; r2 pred/CoMSIA = 0.671). The generated models suggested that electrostatic, hydrophobic, and hydrogen bonding interactions play important roles between ligands and receptors in the active site. Our study serves as a guide for further experimental investigations on the synthesis of new compounds. Structural modifications based on the present 3D-QSAR results may lead to the discovery of other α1A-AR antagonists

Fragment-based design, docking, synthesis, biological evaluation and structure–activity relationships of 2-benzo/benzisothiazolimino–5–aryliden–4-thiazolidinones as cycloxygenase/lipoxygenase inhibitors

Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme's binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/ lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitor

Acetylcholinesterase-Inhibiting Activity of Salicylanilide <em>N</em>-Alkylcarbamates and Their Molecular Docking

A series of twenty-five novel salicylanilide <em>N</em>-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (<em>Electrophorus electricus</em> L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'<sub>(3,4)</sub> of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'<sub>(4)</sub> exhibited slightly more effective AChE inhibitors than in C'<sub>(3)</sub>. Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the <em>N</em>-alkyl chain

Discovery of Novel Focal Adhesion Kinase Inhibitors Using a Hybrid Protocol of Virtual Screening Approach Based on Multicomplex-Based Pharmacophore and Molecular Docking

Focal adhesion kinase (FAK) is a tyrosine kinase that functions as a key orchestrator of signals leading to invasion and metastasis. In the current study, the multicomplex-based pharmacophore (MCBP)-guided method has been suggested to generate a comprehensive pharmacophore of FAK kinase based on seven crystal structures of FAK-inhibitor complexes. In this investigation, a hybrid protocol of virtual screening methods, comprising of pharmacophore model-based virtual screening (PB-VS) and docking-based virtual screening (DB-VS), is used for retrieving new FAK inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen several chemical databases, including the Specs (202,408 compounds) database. Thirty-five compounds were selected from the final hits and should be shifted to experimental studies. These results may provide important information for further research of novel FAK inhibitors