ABSTRACT
A tremendous research on Poly (ADP-ribose) polymerase (PARP) pertaining to cancer and ischemia is in very rapid progress. PARP's are a specific class of enzymes that repairs the damaged DNA. Recent findings suggest also that PARP-1 is the most abundantly expressed nuclear enzyme which involves in various therapeutic areas like inflammation, stroke, cardiac ischemia, cancer and diabetes. The current review describes the overview on clinical candidates of PARP1 and its current status in clinical trials. This paper also covers identification of potent PARP1 inhibitors using structure and ligand based pharmacophore models. Finally 36 potential hits were identified from the virtual screening of pharmacophore models and screened for PARP1 activity. 15 actives were identified as potent PARP1 inhibitors and further optimization of these analogues are in progress.
Subject(s)
Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Clinical Trials as Topic , Enzyme Inhibitors/therapeutic use , Humans , Molecular Docking Simulation , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerase InhibitorsABSTRACT
Structure and ligand based pharmacophore modeling and docking studies carried out using diversified set of c-Jun N-terminal kinase-3 (JNK3) inhibitors are presented in this paper. Ligand based pharmacophore model (LBPM) was developed for 106 inhibitors of JNK3 using a training set of 21 compounds to reveal structural and chemical features necessary for these molecules to inhibit JNK3. Hypo1 consisted of two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), and a hydrophobic (HY) feature with a correlation coefficient (r²) of 0.950. This pharmacophore model was validated using test set containing 85 inhibitors and had a good r² of 0.846. All the molecules were docked using Glide software and interestingly, all the docked conformations showed hydrogen bond interactions with important hinge region amino acids (Gln155 and Met149)and these interactions were compared with Hypo1 features. The results of ligand based pharmacophore model (LBPM)and docking studies are validated each other. The structure based pharmacophore model (SBPM) studies have identified additional features, two hydrogen bond donors and one hydrogen bond acceptor. The combination of these methodologies is useful in designing ideal pharmacophore which provides a powerful tool for the discovery of novel and selective JNK3 inhibitors.
Subject(s)
Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Models, Molecular , Protein Kinase Inhibitors/chemistry , Quantitative Structure-Activity Relationship , Catalytic Domain , Drug Design , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Ligands , Mitogen-Activated Protein Kinase 10/chemistry , Protein Binding , Protein Kinase Inhibitors/metabolism , SoftwareABSTRACT
Bacillus anthracis is a causative organism of anthrax. The main reason to use anthrax as a bioweapon is the combination of the spore's durability and the lethal toxaemia of the vegetative stage. In anthrax infection, lethal factor (LF) is playing crucial role in causing cell death, by inhibiting pathways that rely on this kinase family. The combination of vaccine and antibiotics is preferred as an effective treatment for this target. Till date, no small molecule inhibitor is identified as a drug on the target. In this study, we have performed pharmacophore modeling and docking studies to identify a novel small molecule inhibitor to target the Anthrax LF. The best pharmacophore model is used to screen approximately 2M drug-like small molecule database and yielded 2543 hits. Docking studies of the pharmacophore hits on to the active site of Anthrax LF resulted 120 structurally diverse hits. Out of 120 hits, based on synthetic feasibility, 17 hits are selected for further synthesis and pharmacological screening. In due course, we will publish the updated results.
Subject(s)
Antitoxins/chemistry , Antitoxins/pharmacology , Bacterial Toxins/antagonists & inhibitors , Drug Design , Drug Evaluation, Preclinical , Models, Molecular , User-Computer Interface , Antigens, Bacterial/chemistry , Bacterial Toxins/chemistry , Catalytic Domain , Crystallography, X-Ray , Ligands , Molecular ConformationABSTRACT
Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values <10 microM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.
Subject(s)
Antineoplastic Agents/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Amino Acid Sequence , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Breast Neoplasms , Catalytic Domain , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Ligands , Models, Molecular , Molecular Sequence Data , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quantitative Structure-Activity Relationship , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Receptor, ErbB-2/biosynthesis , Small Molecule LibrariesABSTRACT
In the crystal structure of the title compound, 2C(5)H(5)N(4)O(+)·SO(4) (2-), N-Hâ¯O hydrogen bonds assemble the mol-ecules into a two-dimensional network structure parallel to the cb plane. The S atom of the sulfate ion lies on a special position on a twofold axis.
ABSTRACT
Thromboxane A(2) receptor antagonists have attracted much attention in recent times in the design of new agents that could be active against diseases such as thrombosis, asthma and myocardial ischemia. 3D-QSAR studies have been performed on a series of [[1-aryl(or benzyl)-1-(benzenesulphonamido)methyl] phenyl] alkanoic acid derivatives by using the receptor surface analysis (RSA) method. The RSA analysis was carried out on 31 analogues of which 25 were used in the training set and the rest considered for the test set. This study produced reasonably good predictive models with good cross-validated and conventional r(2) values in both the models.
