Sanggenol B, a plant bioactive, as a safer alternative to tackle cancer by antagonising human FGFR.

Fibroblast Growth Receptor Factor (FGFR) are a family of proteins which are, in addition to their biological role, are involved in various pathological functions, such as cancer cellular proliferation, and metastasis. Deregulation of FGFRs at various points could result in malignancy. A conformational transition of the DFG (Asp-Phe-Gly) motif can switch the enzyme from a catalytically active (DFG-in) to an inactive (DFG-out) state. There are a few FDFR inhibitors which have received approval from the FDA, but these have adverse side effects. Hence, there is a demand for safer alternatives. With this aim, Ligand and Structure based virtual screening was carried to identify suitable lead molecule. In this process, Four Featured atom-based 3D Pharmacophore with quantitative structure-activity relationship analysis (3D-QSAR) was developed. The External validation of the hypothesis was carried invoking criteria such as Area under the ROC curve. Natural plant compound databases such as the Traditional Chinese medicine, NPACT and the ZINC Natural databases were chosen for pharmacophore filtering, which was followed by virtual screening against FGFR isoforms. The compound Sanggenol B was identified as the most suitable lead molecule. Structural stability of the protein-ligand complex and interactions of the ligand (Sanggenol B & the reference compound Ponatinib) with FGFR were analysed for 1000 ns (triplicate) by means of molecular simulation and the binding free energy was calculated using MMGBSA. Sanggenol B (PubChem CID: 15233694) binds effectively at the active site with favourable energies and is proposed as a safe alternative from a natural source.Communicated by Ramaswamy H. Sarma.

Electronic effect-dependent intramolecular non-covalent interactions on the activity of 4,4-dimethylimidazolidin-2-one pharmacophore-based androgen receptor antagonists.

Because androgen receptor (AR) signalling is important for the development and progression of prostate cancer (PC), AR antagonists are utilized in clinical practices to treat PC and are referred to as androgen deprivation therapy (ADT). However, continued administration of AR antagonists often results in the development of resistance, known as castration-resistant prostate cancer (CRPC). Despite castration, it has been demonstrated that AR signalling continues to be fundamental to tumour growth. In this regard, a series of readily synthesizable 4,4-dimethylimidazolidine-2-one pharmacophore-based AR antagonists (FAR01-FAR11) were designed and synthesized. Androgen-dependent LNCaP PC cell line was used to test the AR-antagonist activity of these compounds in vitro and compared with the U.S. Food and Drug Administration (FDA) approved second-generation enzalutamide. In our previous work, rigid thiohydantoin pharmacophore in enzalutamide is replaced by the flexible 4,4-dimethylimidazolidin-2-one. In order to improve the flexibility further, one methylene group is introduced between the pharmacophore and one of the aromatic ring. Despite the fact that the amide functional group is a crucial characteristic for building AR antagonists, this class of molecules lacks one. FAR06 has the exact same activity as enzalutamide (IC50 : 0.782 µM) with an IC50 value of 0.801 µM among the series of compounds.

Epigallocatechin Gallate with Potent Anti-Helicobacter pylori Activity Binds Efficiently to Its Histone-like DNA Binding Protein.

Helicobacter pylori (H. pylori)-a human gastric pathogen-forms a major risk factor for the development of various gastric pathologies such as chronic inflammatory gastritis, peptic ulcer, lymphomas of mucosa-associated lymphoid tissues, and gastric carcinoma. The complete eradication of infection is the primary objective of treating any H. pylori-associated gastric condition. However, declining eradication efficiencies, off-target effects, and patient noncompliance to prolong and broad-spectrum antibiotic treatments has spurred the clinical interest to search for alternative effective and safer therapeutic options. As natural compounds are safe and privileged with high levels of antibacterial-activity, previous studies have tested and reported a plethora of such compounds with potential in vitro/in vivo anti-H. pylori activity. However, the mode of action of majority of these natural compounds is unclear. The present study has been envisaged to compile the information of various such natural compounds and to evaluate their binding with histone-like DNA-binding proteins of H. pylori (referred here as Hup) using in silico molecular docking-based virtual screening experiments. Hup-being a major nucleoid-associated protein expressed by H. pylori-plays a strategic role in its survival and persistent colonization under hostile stress conditions. The ligand with highest binding energy with Hup-that is, epigallocatechin-(-)gallate (EGCG)-was rationally selected for further computational and experimental testing. The best docking poses of EGCG with Hup were first evaluated for their solution stability using long run molecular dynamics simulations and then using fluorescence and nuclear magnetic resonance titration experiments which demonstrated that the binding of EGCG with Hup is fairly strong (the resultant apparent dissociation constant (k D) values were equal to 2.61 and 3.29 ± 0.42 µM, respectively).

Identification of novel Nicotinamide Phosphoribosyltransferase (NAMPT) inhibitors using computational approaches.

Nicotinamide Phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of NAD. Cancer cells have elevated poly [ADP-Ribose] polymerase 1 (PARP) activity as well as the immense necessity of ATP: thereby consuming NAD at a higher rate than normal tissues. The perturbation of these intracellular processes is more sensitive and highly dependent on NAMPT to maintain the required NAD levels. Functional inhibition of NAMPT is, therefore, a promising drug target in therapeutic oncology. In this study, the importance of intermolecular contacts was realized based on contact occupancy and favorable energetic from molecular dynamic simulation to discern non-critical contacts of four different classes of potential NAMPT inhibitor bound complexes. Further, pharmacophore modeling, molecular docking, a quantum mechanical properties and MD simulation, as well as active site residual network communication were employed to identify potential leads. Present studies identified two leads, 2 and 3 which have better binding free energy compared to known inhibitors and showed stable hydrogen bonding and hydrophobic contacts with ß barrel cavity lining residues in the active site of the dimer interface (A'B). Lead 2 containing fluorene as central core and lead 3 having phenyl-benzamide as a core showed stable moiety which was observed from electronic property analysis. Active site residual communication in identified leads bound complex also showed similarity to known inhibitor complexes. Compounds containing these moieties were not reported until now against NAMPT inhibition and can be considered as novel cores for future development of drugs to inhibit NAMPT function.