Structure-based virtual screening,molecular docking,ADMET and molecular simulations to develop benzoxaborole analogs as potential inhibitor against Leishmania donovani trypanothione reductase

Visceral leishmaniasis (VL) is the most fatal form of leishmaniasis and it affects 70 countries worldwide. Increasing drug resistant for antileishmanial drugs such as miltefosine, sodium stibogluconate and pentamidine has been reported in the VL endemic region. Amphotericin B has shown potential antileishmanial activity in different formulations but its cost of treatment and associated nephrotoxicity have limited its use by affected people living in the endemic zone. To control the VL infection in the affected countries, it is necessary to develop new antileishmanial compounds with high efficacy and negligible toxicity. Computer aided programs such as binding free energy estimation; ADMET prediction and molecular dynamics simulation can be used to investigate novel antileishmanial molecules in shorter duration. To develop antileishmanial lead molecule, we performed standard precision (SP) docking for 1160 benzoxaborole analogs along with reference inhibitors against trypanothione reductase of Leishmania parasite. Furthermore, extra precision (XP) docking, ADMET prediction, prime MM-GBSA was conducted over 115 ligands, showing better docking score than reference inhibitors to get potential antileishmanial compounds. Simultaneously, area under the curve (AUC) was estimated using ROC plot to validate the SP and XP docking protocol. Later on, two benzoxaborole analogs with best MM-GBSA ΔG-bind were subjected to molecular simulation and docking confirmation to ensure the ligand interaction with TR. The presented drug discovery based on computational study confirms that BOB27 can be used as a potential drug candidate and warrants further experimental investigation to fight against VL in endemic areas.     

Artificial intelligence in differentiating tropical infections: A step ahead

Background and objectiveDifferentiating tropical infections are difficult due to its homogenous nature of clinical and laboratorial presentations among them. Sophisticated differential tests and prediction tools are better ways to tackle this issue. Here, we aimed to develop a clinician assisted decision making tool to differentiate the common tropical infections.MethodologyA cross sectional study through 9 item self-administered questionnaire were performed to understand the need of developing a decision making tool and its parameters. The most significant differential parameters among the identified infections were measured through a retrospective study and decision tree was developed. Based on the parameters identified, a multinomial logistic regression model and a machine learning model were developed which could better differentiate the infection.ResultsA total of 40 physicians involved in the management of tropical infections were included for need analysis. Dengue, malaria, leptospirosis and scrub typhus were the common tropical infections in our settings. Sodium, total bilirubin, albumin, lymphocytes and platelets were the laboratory parameters; and abdominal pain, arthralgia, myalgia and urine output were the clinical presentation identified as better predictors. In multinomial logistic regression analysis with dengue as a reference revealed a predictability of 60.7%, 62.5% and 66% for dengue, malaria and leptospirosis, respectively, whereas, scrub typhus showed only 38% of predictability. The multi classification machine learning model observed to have an overall predictability of 55–60%, whereas a binary classification machine learning algorithms showed an average of 79–84% for one vs other and 69–88% for one vs one disease category.ConclusionThis is a first of its kind study where both statistical and machine learning approaches were explored simultaneously for differentiating tropical infections. Machine learning techniques in healthcare sectors will aid in early detection and better patient care.     

Reproductive behaviour and semen characteristics in experimental hypothyroidism in goats

Hypothyroidism was induced in goats using thiourea as the goitrogen for 90 days and the reproductive behaviour and semen characteristics were studied. The reversability of the changes was also observed for 90 days on discontinuation of treatment with thiourea. Loss of libido in males and anoestrum in females were the important clinical features observed in hypothyroid animals. There was a decrease in ejaculate volume, sperm concentration, motility and viability with an increased incidence of abnormal spermatozoa. There was significant improvement in the quality and quantity of semen when the animal became euthyroid after withdrawal of thiourea.     

In vitro antioxidant profile of phenolic acid derivatives

Several caffeic acid esters isolated from propolis exhibit interesting antioxidant properties, but their in vivo use is compromised by hydrolysis of the ester bond in the gastrointestinal tract. Therefore, a series of caffeic acid amides were synthesized and their in vitro antioxidant profile was determined. A series of hydroxybenzoic acids, hydroxycinnamic acids, and the synthesized caffeic acid amides were tested for both their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and microsomal lipid peroxidation-inhibiting activity. Some of the highly active antioxidants were further tested by means of electron paramagnetic resonance for their hydroxyl radical scavenging activity. Since a promising antioxidant compound should show a lipid peroxidation-inhibiting activity at micromolar level and a low cytotoxicity, the cytotoxicity of the phenolic compounds was also studied. In all the assays used, the caffeic acid anilides and the caffeic acid dopamine amide showed an interesting antioxidant activity.     

Caenorhabditis elegans functional genomics: omic resonance.

The nematode Caenorhabditis elegans is widely used as a model organism for studying many fundamental aspects of development and cell biology, including processes underlying human disease. The genome of C. elegans encodes over 19,000 protein-coding genes and hundreds of non-coding RNAs. The availability of whole genome sequence has facilitated the development of high throughput techniques for elucidating the function of individual genes and gene products. Furthermore, attempts can now be made to integrate these substantial functional genomics data collections and to understand at a global level how the flow of genomic information that is at the core of the central dogma leads to the development of a multicellular organism.     

Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma.

OBJECTIVE--To assess the risk of second brain tumour in patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. DESIGN--Long term follow up of a cohort of patients with pituitary adenoma and comparison of tumour occurrence with population incidence rates. SETTING--The Royal Marsden Hospital. SUBJECTS--334 patients with pituitary adenoma treated with conservative surgery and radiotherapy (median dose 45 Gy) and followed up for 3760 person years. MAIN OUTCOME MEASURES--Second intracranial tumour and systemic malignancy. RESULTS--Five patients developed a second brain tumour: two had astrocytoma, two meningioma, and one meningeal sarcoma. The cumulative risk of developing a second brain tumour over the first 10 years after treatment was 1.3% (95% confidence interval 0.4% to 3.9%) and over 20 years 1.9% (0.7% to 5.0%). The relative risk of a second brain tumour compared with the incidence in the normal population was 9.38 (3.05 to 21.89). There was no excess risk of any other type of second primary malignancy. CONCLUSIONS--There is an increased risk of second intracranial tumour in patients with pituitary adenoma treated with surgery and radiotherapy. Although radiation is likely to be the most important factor contributing to the excess risk, further study is required in a cohort of similar patients not receiving radiation.     

Metal chelates in the storage and transport of neurotransmitters: formation of mixed ligand chelates of Mg 2+ -ATP with biogenic amines

Abstract— Quantitative studies on the interactions of adenosine-triphosphate and several biogenic amines with magnesium ion have been carried out in an attempt to correlate the thermodynamic stabilities of the metal-binding of the amines with the in vivo affinities of the amines for granule-binding. Equilibrium data indicate that in each of the ternary chelate systems (viz. Mg²⁺-ATP-amine), the predominant reaction in the pH range 3.0–7.0 is the formation of a magnesium-ATP chelate with a stability constant, log K_ML=3.22 ± 0.02. Each of the biogenic amines coordinates with Mg²⁺-ATP system in the pH range 7.0–10.5 to form the mixed ligand chelate (or ternary chelate), Mg²⁺-ATP-amine(1:1:1). The stability constants for the binding of the amines with Mg²⁺-ATP are: (i) norepinephrine (NE) = 2.34 ± 0.32; (ii) epinephrine (E) = 2.95 ± 0.08; (iii) dopamine (DA) = 3.05 ± 0.06; (iv) octopamine (OA) = 1.93 ± 0.12; (v) 6-hydroxydopamine (6-HDA) = 2.42 ± 0.14; (vi) 3-methoxynorephedrine (MeN) =2.76 ± 0.09; (vii) amphetamine (AA) =2.09 ± 0.05; (viii) tyramine (TA) = 2.60 ± 0.04; (ix) phenylethylamine (PEA) = 0. A general correlation is indicated between the stability constants (binding strengths) of the amine chelates and the metal-binding functionalities of the amines on the one hand and their vesicular binding characteristics in in vivo systems on the other (Carlsson and Waldeck , 1966). The Mg²⁺-ATP-dependant amine storage mechanism of KIRSHNER (1962a;b) and Carlsson , Hillårp and Waldeck (1963) is discussed both in the light of the data on metal chelate stability and of a significant modification of metal coordination hypothesis.     

Proteasomal dysfunction and ER stress triggers 2′-hydroxy-retrochalcone-induced paraptosis in cancer cells

Chalcones are biologically active class of compounds, known for their anticancer activities. Here we show for the first time that out of the six synthetic derivatives of chalcone tested, 2′-hydroxy-retrochalcone (HRC) was the most effective in inducing extensive cytoplasmic vacuolation mediated death called paraptosis in malignant breast and cervical cancer cells. The cell death by HRC is found to be nonapoptotic in nature due to the absence of DNA fragmentation, PARP cleavage, and phosphatidylserine externalization. It was also found to be nonautophagic as there was an increase in the levels of autophagic markers LC3I, LC3II and p62. Immunofluorescence with the endoplasmic reticulum (ER) marker protein calreticulin showed that the cytoplasmic vacuoles formed were derived from the ER. This ER dilation was due to ER stress as evidenced from the increase in polyubiquitinated proteins, Bip and CHOP. Docking studies revealed that HRC could bind to the Thr1 residue on the active site of the chymotrypsin-like subunit of the proteasome. The inhibition of proteasomal activity was further confirmed by the fluorescence based assay of the chymotrypsin-like subunit of the 26S proteasome. The cell death by HRC was also triggered by the collapse of mitochondrial membrane potential and depletion of ATP. Pretreatment with thiol antioxidants and cycloheximide were able to inhibit this programmed cell death. Thus our data suggest that HRC can effectively kill cancer cells via paraptosis, an alternative death pathway and can be a potential lead molecule for anticancer therapy.