Three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis and molecular docking-based combined in silico rational approach to design potent and novel TRPV1 antagonists

The discovery of clinically relevant antagonists of TRPV1 for neuropathy pain therapy has proven to be a challenging task. For better understanding of the molecular interactions of antagonists with TRPV1 receptor, a series of chroman and tetrahydroquinoline ureas were analyzed by k-nearest neighbor molecular field analysis (kNN-MFA) and molecular docking. To elucidate the structural properties required for activity as TRPV1 antagonists, we report here kNN-MFA-based 3D-QSAR model for chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists. Sphere exclusion method was used for dividing the compounds into training (26 compounds) and test (5 compounds) set. Overall model classification accuracy was 81.35 % (q ² = 0.8135, representing internal validation) in training set and 81.44 % (pred_r ² = 0.8144, representing external validation) in test set using stepwise forward as a method of variable selection. The stereo view of molecular rectangular grid field of 3D-QSAR using this approach showed that steric and hydrophobic effects dominantly determine binding affinities. Furthermore, the crystal structure of TRPV1 was obtained from protein data bank (PDB code 2NYJ, resolution 3.20 Å), and docking of 31 TRPV1 antagonists into putative binding sites of the TRPV1 were studies. Molecular docking was employed to explore the binding mode between these compounds and the receptor, as well as help understanding the structure–activity relationship revealed by kNN-MFA. Our QSAR model and molecular docking results corroborate with each other and propose directions for the design of new antagonists with better activity toward TRPV1.     

Severe wasting among Indian infants <6 months: Findings from the National Family Health Survey 4

Burden and risk factors for wasting in the first 6 months of life among Indian children are not well documented. We used data from India's National Family Health Survey 4 to estimate the prevalence of severe wasting (weight for length < ‐3 SD) among 18,898 infants under 6 months of age. We also examined the association of severe wasting with household, maternal, and child‐related factors using multivariable logistic regression analysis. Prevalence of severe wasting among infants less than 6 months of age was 14.8%, ranging from 3.5 to 21% across states. Low birth weight (<2,500 g; adjusted odds ratio [AOR] 1.40, 95% CI [1.19, 1.65]), nonutilization of supplementary nutrition by mother during lactation (AOR 1.23, 95% CI [1.05, 1.43]), and anthropometric assessment during summer (AOR 1.37, 95% CI [1.13, 1.65]) and monsoon months (AOR 1.53, 95% CI [1.20, 1.95]) were associated with higher odds of severe wasting. Infants aged 2 to 3 months (AOR 0.78, 95% CI [0.66, 0.93]) and 4 to 5 months (AOR 0.65, 95% CI [0.55, 0.73]) had lower odds of severe wasting as compared with the 0‐ to 1‐month category. This analysis reveals a high burden of severe wasting in infants less than 6 months in India. Preventive interventions must be targeted at reducing low birth weight due to fatal growth restriction and prematurity. Appropriate care practices at facilities and postdischarge with extra attention to those born small and sick can prevent further deterioration in nutritional status.     

Fabrication and design of transdermal fluconazole spray

The objective of the present study was to formulate fluconazole transdermal spray for obtaining modified drug transport using eutectic mixture, ethyl cellulose, polyethylene oxide and alcohol. The formulated products were characterized. The selection of the optimized batch was done considering the results of drug transport in the first hour, the time required for 90% drug transport, viscosity and spray angle of the formulations. The inclusion of eutectic mixture, consisting of equal parts of camphor and menthol, showed improved drug transport through rat skin. The optimized batch exhibited larger mean zone of inhibition (antifungal activity), efficient in vivo activity and short term stability.