Virtual screening, identification and experimental testing of novel inhibitors of PBEF1/Visfatin/NMPRTase for glioma therapy

Background: Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes nicotinamide phosphoribosyltransferase (NMPRTase), which catalyses the rate limiting step in the salvage pathway of NAD+ metabolism in mammalian cells. PBEF1 transcript and protein levels have been shown to be elevated in glioblastoma and a chemical inhibitor of NMPRTase has been shown to specifically inhibit cancer cells. Methods: Virtual screening using docking was used to screen a library of more than 13,000 chemical compounds. A shortlisted set of compounds were tested for their inhibition activity in vitro by an NMPRTase enzyme assay. Further, the ability of the compounds to inhibit glioma cell proliferation was carried out. Results: Virtual screening resulted in short listing of 34 possible ligands, of which six were tested experimentally, using the NMPRTase enzyme inhibition assay and further with the glioma cell viability assays. Of these, two compounds were found to be significantly efficacious in inhibiting the conversion of nicotinamide to NAD+, and out of which, one compound, 3-amino-2-benzyl-7-nitro-4-(2-quinolyl-)-1,2-dihydroisoquinolin-1-one, was found to inhibit the growth of a PBEF1 over expressing glioma derived cell line U87 as well. Conclusions: Thus, a novel inhibitor has been identified through a structure based drug discovery approach and is further supported by experimental evidence

LuxS gene: Molecular docking and virtual screen analysis of Staphylococcus hominis

1189-1197Staphylococcus hominis plays a vital role in causing pathogenic infections in marine animals. In recent years, natural compounds from marine resources have gained interest owing to their potential effect against multidrug-resistant bacteria. LuxS gene is an important virulence factor needed to coordinate the biofilm production but no structural information is available for LuxS protein. To identify the homology model and to validate LuxS protein structure, an investigation was carried out using Modeller software. Molecular dynamics analysis was performed using a Desmond protocol. Molecular docking studies were carried out using marine compounds to suppress the LuxS protein, and antibiotics were also docked. Virtual screening was performed with LuxS protein against binding (CID-11446) dock score (-9.647) and Maybridge databases (CID-9017) docking score (-9.820) to find the potential compounds which provide better results than marine compounds. On the basis of the findings, it is concluded that the marine compound Aerobactin (CID-123762) is a potential inhibitor for LuxS protein in S. hominis with the highest dock score of -10.337, having eight hydrogen bonding interactions. Hence the compound could be further exploited for producing a drug against S. hominis

Triagem virtual de potenciais ligantes para a oncoproteína E6 do HPV tipo 16

Trabalho de Conclusão de Curso (Graduação)O Vírus do Papiloma Humano (HPV) é responsável por ser uma das causas principais de diversos tipos de câncer, como o de colo de útero, que é uma das principais causas de morte em todo mundo. Existem mais de 200 tipos de HPV identificados, dentro os quais os tipos 16 e 18 são os mais relacionados com o câncer de colo de útero. O vírus codifica duas proteínas que são conhecidas por desempenhar um papel crucial no desenvolvimento do câncer, a E6 e a E7. Estas oncoproteínas são capazes de alterar vias de regulação no controle do ciclo celular, neutralizando uma das proteínas importantes supressoras de tumores, a p53. Dessa forma, há uma clara importância em desenvolver novas abordagens para o tratamento contra HPVs de alto risco para o câncer, visto que ainda não há uma forma inteiramente eficiente nos estudos atuais. Este trabalho utilizou da técnica de triagem virtual e docagem molecular com o intuito de encontrar um potencial ligante para as proteínas oncogênicas de forma a impedir a proliferação do tumor. Assim foi possível selecionar compostos com maior afinidade à proteína E6 do HPV tipo 16 utilizando de banco de dados de moléculas com características druglike e compostos naturais

Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.</jats:p

Molecular Targets of CNS Tumors

Molecular Targets of CNS Tumors is a selected review of Central Nervous System (CNS) tumors with particular emphasis on signaling pathway of the most common CNS tumor types. To develop drugs which specifically attack the cancer cells requires an understanding of the distinct characteristics of those cells. Additional detailed information is provided on selected signal pathways in CNS tumors