Identification of novel human nicotinamide N-methyltransferase inhibitors: a structure-based pharmacophore modeling and molecular dynamics approach.

Human nicotinamide N-methyltransferase (hNNMT) is a cytosolic enzyme associated in the phase-II metabolism, belonging to the S-adenosyl-L-methionine (SAM)-dependent methyltransferases family. Overexpression of hNNMT was observed in diseases such as metabolic disorders and different types of cancers, which suggest NNMT as a prospective therapeutic target. In this study we propose a structure-based pharmacophore model to understand the structural features responsible for the pharmacological activity. The generated model was validated using the ROC curve (AUC), goodness of hit score (GH), specificity, sensitivity and enrichment factor (EF). The pharmacophore was employed to retrieve active molecules from the ZINC database, followed by virtual-screening and molecular docking. Six molecules with the best pharmfit score, binding energy and ADMET properties were identified in this study. A 150 ns molecular dynamics simulation was performed on the selected molecules complexed with hNNMT protein to validate the results. The molecules ZINC35464499, ZINC13311192, ZINC31159282, ZINC14650833, ZINC14819515 and ZINC00303881 were identified, which could be act as the potential hNNMT inhibitors and can also be used as direct hits for developing novel hNNMT antagonists.Communicated by Ramaswamy H. Sarma.

A novel photosensitizer: An l-glutamide lipid conjugate with improved properties for photodynamic therapy.

Photosensitizers (PS) are used in photodynamic therapy to treat several cancers. The efficacy of photodynamic therapy (PDT) could be further improved by overcoming aggregation-dependent quenching of PS and by improving the biodistribution of the PS. In this work we attempted to overcome these issues by conjugating a PS with a lipid molecule and tested the liposomes prepared with this PS conjugated lipid for PDT. A novel lipid-porphyrin conjugate (1 : 1) was synthesized by attaching a PS, 5-(4-methoxycarbonylphenyl)-10,15,20-triphenyl-21H,23H-porphine, to the head group of a glutamide lipid. Two liposomal preparations, with egg phosphatidylcholine as the bulk lipid, were prepared viz. liposomes with PS conjugated lipid (LPSL) and PS entrapped in liposomes (PSL). At equimolar concentrations of the PS, both liposomal preparations were found to generate comparable amounts of reactive oxygen species as free PS upon light exposure. Electron micrographs and dynamic light scattering measurements indicated uniform and circular liposomes of 150 nm in size and near neutral zeta potential. Uptake of these liposomes by the human ovarian carcinoma cell line, SK-OV-3, was shown by FACS and confocal microscopy. Upon light exposure, the LPSL, i.e., with the conjugate lipid, have shown a substantial decrease (>4 times) in the PS requirement compared to PSL or free PS in its ability to cause light mediated cell death of SK-OV-3 cells. The light mediate cell death by LPSL was shown to be not dependent on the bulk properties of the lipid. Our data suggest a potential benefit of conjugating PS with a lipid in improving the efficiency of PDT.