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.     

Clinicopathological Profile of Myelomatous Pleural Effusion: Single-center Real-world Experience and Review of Literature

Background

Multiple myeloma (MM) is a hematologic malignancy of plasma cell origin. MM primarily affects bone marrow, but extramedullary sites can also be involved. Myelomatous pleural effusion (MPE) is an atypical and rare complication of MM. We aimed to systematically study the incidence and clinicopathologic profile of patients with MPE in a real-world setting.

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

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Pharmacokinetics and brain penetration study of chlorogenic acid in rats

1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles–Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path.

2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10?mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method.

3. The study observes that CGA is rapidly absorbed in plasma with t_max of 1?min similar to IV route after IN administration. The peak plasma concentration and AUC_0–24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route.

4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360?min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUC_{brain, IN}) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUC_{brain, IV}) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders.     

Dynamic Changes with Liver Atrophy as an Alternate Marker of Chemotherapy-Associated Liver Injury

Annals of Surgical Oncology -     

Isolation and analysis of partial cDNA sequence coding for superoxide dismutase in Wuchereria bancrofti.

Molecular characterization of Wuchereria bancrofti is essential to develop suitable anti-filarial drugs and vaccines. We describe here isolation, sequence analysis and cloning of a partial cDNA of an enzyme superoxide dismutase from this parasite. The immunoscreening of a lambda zap W. bancrofti microfilarial (Mf) cDNA library with microfilaremic sera had resulted in the isolation of several seroreactive clones including, WbSOD. This clone contained a 309 bp insert and showed significant nucleotide and deduced amino acid sequence homologies to the superoxide dismutases of other nematode parasites. The antioxidant property of this enzyme may have important contribution in the defense mechanism of the parasite against host immune response.     

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