3D QSAR and pharmacophore studies on inhibitors of insuline like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) as potential anti-cancer agents

Insulin like growth factor receptor (IGF-1R) and Insulin receptor (IR) are widely accepted to play a prominent role in cancer drug discovery due to their well-established involvement in various stages of tumorigenesis. Previously, neutralization of IGF-1R via monoclonal antibodies was in focus, which failed because of compensatory activation of IR-A upon inhibition of IGF-1R. Recent studies have demonstrated high homology between IGF-IR and IR particularly in tyrosine kinase domain and targeting both receptors have produced efficient therapeutic approaches such as inhibition of cancer cell cycle proliferation. Herein, we have made an attempt to analyze the unique data set from different chemical classes, containing potent ATP competitors against tyrosine kinase domain. We performed the 2D, 3D quantitative structure–activity relationship (QSAR) studies on inhibitors of these receptors to predict useful pharmacophoric features. We have optimized virtual screening of structurally diverse data set of dual inhibitors of IGF-1R and IR. Based on QSAR studies, we predict potential novel clinical candidates with a demonstrated absorption, distribution, metabolism, elimination, and toxicology (ADMETox) track. We also demonstrated comprehensive analysis of co–crystal complexes along with their inhibitors and built 3D- GRid INdependent Descriptors (GRIND) model to obtain insightful features such as H-bond donors and acceptors, overall topology and Vander Waal volume (vdw_vol) which are found to be responsible for dual inhibition of receptors. These findings lead to further description that Tirofiban, Practolol, Edoxaban, Novobiocin have potential to perform dual inhibition of both targets

Generation of polyclonal antibody with high avidity to rosuvastatin and its use in development of highly sensitive ELISA for determination of rosuvastatin in plasma

In this study, a polyclonal antibody with high avidity and specificity to the potent hypocholesterolaemic agent rosuvastatin (ROS) has been prepared and used in the development of highly sensitive enzyme-linked immunosorbent assay (ELISA) for determination of ROS in plasma. ROS was coupled to keyhole limpt hemocyanin (KLH) and bovine serum albumin (BSA) using carbodiimide reagent. ROS-KLH conjugate was used for immunization of female 8-weeks old New Zealand white rabbits. The immune response of the rabbits was monitored by direct ELISA using ROS-BSA immobilized onto microwell plates as a solid phase. The rabbit that showed the highest antibody titer and avidity to ROS was scarified and its sera were collected. The IgG fraction was isolated and purified by avidity chromatography on protein A column. The purified antibody showed high avidity to ROS; IC50 = 0.4 ng/ml. The specificity of the antibody for ROS was evaluated by indirect ELISA using various competitors from the ROS-structural analogues and the therapeutic agents used with ROS in a combination therapy. The proposed ELISA involved a competitive binding reaction between ROS, in plasma sample, and the immobilized ROS-BSA for the binding sites on a limited amount of the anti-ROS antibody. The bound anti-ROS antibody was quantified with horseradish peroxidase-labeled second anti-rabbit IgG antibody (HRP-IgG) and 3,3',5,5'-tetramethylbenzidine (TMB) as a substrate for the peroxidase enzyme. The concentration of ROS in the sample was quantified by its ability to inhibit the binding of the anti-ROS antibody to the immobilized ROS-BSA and subsequently the color intensity in the assay wells. The assay enabled the determination of ROS in plasma at concentrations as low as 40 pg/ml

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

An observational study to evaluate the efficacy of Saha Ashwagandhadi Taila Nasya and Balashatavaryadi Ghrita Tarpana in Prathama Patalagata Timira with special reference to Simple Myopia

Introduction: Prathama Patalagata Timira is one of the stages of Timira which is a Drishtigata Roga and can be correlated to Simple Myopia with the characteristic symptom of blurred vision for distant objects. This disease is said to be physiological and become the major health concern. It is the common cause of ocular morbidity that may ultimately lead to blindness as explained by Vagbhatacharya. Objectives: The objectives of the study are to evaluate efficacy of Nasya and Tarpana in relieving Myopia & Asthenopic symptoms such as head ache, eye strain, watering of the eyes. Methods: 30 patients fulfilling the inclusion criteria of simple myopia were randomly selected. Nasya with Saha Ashwagandhadi taila for 7 days then from 8th day Tarpana with Balashatavaryadi Ghrita was done for 7 days, followed by 2 follow-ups. Results: The overall assessment was done before treatment, on 15th day, 30th day and 44th day. Conclusion: Nasya has role in improving vision where as Tarpana relieves asthenopic symptoms as well as improves vision

An efficient ultrasound-assisted zinc reduction of fatty esters containing conjugated enynol and conjugated enynone systems

Reduction of methyl 8-hydroxy-11-E/Z-octadecen-9-ynoate (1) with zinc in either aqueous n-propanol or water under concomitant ultrasound irradiation furnished a mixture of methyl 8-hydroxy-9Z,11E-octadecadienoate (3a) and methyl 8-hydroxy-9Z, 11Z-octadecadienoate (3b) (96% yield). Reduction of methyl 8-oxo-11-E/Z-octadecen-9-ynoate (2) under similar conditions gave methyl 8-oxo-10-Z-octadecenoate exclusively (4, 70%). The latter compound was epoxidized and converted to a C18 furanoid fatty ester (6, methyl 8,11-epoxy-8,10-octadecadienoate) in 70% yield

Effects of a novel ACE inhibitor, 3-(3-thienyl)-L-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in L-NAME-induced hypertensive rats

Mahesh Kumar Seth,1–3 M Ejaz Hussain,2 Santosh Pasha,1 Mohammad Fahim3 1Peptide Synthesis Laboratory, CSIR, Institute of Genomics and Integrative Biology, Delhi, India; 2Centre for Physiotherapy and Rehabilitation Sciences, Jamia Millia Islamia, New Delhi, India; 3Department of Physiology, Jamia Hamdard Deemed University, New Delhi, India Abstract: Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by NG-nitro-L-arginine methyl ester (ʟ-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-ʟ-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin–angiotensin–aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in ʟ-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in ʟ-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the ʟ-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the ʟ-NAME model. Keywords: nitric oxide, ACE inhibito