Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Short-Duration Prednisolone in Children with Nephrotic Syndrome Relapse: A Noninferiority Randomized Controlled Trial

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Neonatal renal failure due to obstructive candidal bezoars

Acute renal failure (ARF) developed in a 7-week-old infant due to bilateral candidal bezoars (fungal balls) causing obstruction at the pelviureteric junction. The baby was born at term with an appropriate birthweight, and had been treated with broad-spectrum antibiotics for respiratory distress and septicemia during the 1st week of life. Recovery from ARF followed renal decompression with bilateral nephrostomy tube placement and parenteral administration of amphotericin B and 5-flucytosine. Received August 21, 1996; received in revised form and accepted January 3, 1997     

Musical obsession or pseudohallucination: Electrophysiological standpoint

Reported herein is a case of obsessive–compulsive disorder with persistent and distressing musical obsessions along with other symptoms. Advanced source analysis of electroencephalographic data indicated high spectral power over the bifrontal region. The musical symptoms were resistant to pharmacotherapy but there was some reduction in frequency and duration of musical obsessions with thought-stopping technique.     

Skeletonised retrograde distal perforator island fasciocutaneous flaps for leg and foot defects.

Defects involving the distal leg and foot are frequently encountered following various aetiological factors. Paucity of local tissue causes surgeons to resort to the retrograde peninsular flap, the cross leg flap or the free flap. With specific knowledge of perforators, the fasciocutaneous flap from the calf area can be transferred to the defect in a single stage based on skeletonised distal perforators. The surgical anatomy, flap planning and procedure have been detailed. Nineteen patients were treated during the period 1995 to 2005. The perforators were identified preoperatively by audio Doppler. The flaps were marked and dissected proximal to the defect skeletonising the distal perforators under loupe magnification and transferred to the defect in a single stage. The donor site was skin grafted. Out of 19 cases, 16 flaps healed uneventfully, one flap necrosed completely and in two cases there was marginal necrosis. The cases were followed up for 2-10 years with an average of 6 years. With detailed knowledge of perforators one can safely reconstruct distal moderate-size defects of the lower limb in a single stage, thus having the benefits of free tissue transfer without resorting to microsurgery. This technique has proved to be an advancement in the reconstructive repertoire allowing flaps of non conventional dimensions to be perfused by skeletonised perforators.