Active and allosteric site binding MM-QM studies of Methylidene tetracyclo derivative in PCSK9 protein intended to make a safe antilipidemic agent.

Interaction of low-density lipoprotein receptors with proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital part in causing atherosclerosis. It is the hidden precursor of clinical myocardial infarction (MI), stroke, CVD and estimates 60% of deaths worldwide. The current need is to design small molecules to prevent the interaction between PCSK9 and LDL receptors. This study aims to evaluate the interaction between Methylidene tetracyclo derivative and PCSK9 protein through conceptual studies and compare the same with the interaction of the standard atorvastatin. Also, a comparative study was performed to analyze the interaction of molecules inside the active and allosteric sites of PCSK9. The RCSB downloaded pdb file 7S5H and the above said ligands were optimized to the level of local minima energy and configured inside the active and allosteric sites. The stability of non-bonded interactions of the complexes were analyzed using Desmond MD simulation studies. The results of docking showed that the Methylidene tetracyclo molecule possesses a two-fold higher affinity of -10.894 kcal/mol in the active site and -10.884 kcal/mol in the allosteric site. The Phe379 amino acid enabled the Methylidene tetracyclo molecule to orient inside the active site. Nine H-bonds with 6 amino acids of allosteric site increased the binding affinity compared to Atorvastatin. The MD simulation studies confirmed the stability of the nonbonded interaction of Methylidene tetracyclo molecule throughout 100 ns. This confirms that the Methylidene tetracyclo molecule will be the better hit as well as the lead molecule to modulate the behavior of PCSK9 protein.Communicated by Ramaswamy H. Sarma.

Green synthesis of zinc oxide nanoparticles using leaf extracts of Raphanus sativus var. Longipinnatus and evaluation of their anticancer property in A549 cell lines.

In 21 st century, nanomedicine has turned out to be an emergent modulus operation for the diagnosis and treatment for cancer. The current study includes the Green synthesis of zinc oxide nanoparticles (ZnO NPs) from the leaves of Raphanus sativus var. Longipinnatus and interpretation of its anticancer activity. Synthesized ZnO NPs were investigated by UV-vis, FTIR, particle size analysis, SEM, XRD and its anticancer activity using A549 cell lines. The UV-vis and particle size confirmed the developed ZnO NPs are in nanoscale. The FTIR studies confirmed the presence of various functional groups. SEM and XRD pictures confirmed the partial crystal spherical shape and wurtzite crystal nature. The cytotoxicity results pointed out the enhanced cytotoxic effect of the synthesized ZnO NPs. This is the first attempt of Raphanus sativus var. Longipinnatus facilitated synthesis of ZnO NPs as anticancer agents and may subsequently be potential chemopreventive agent against other cancer treatment in future.

Atypical Antidepressant Activity of 3,4-Bis(3,4-Dimethoxyphenyl) Furan-2,5-Dione Isolated from Heart Wood of Cedrus deodara, in Rodents.

Cedrus deodara (Pinaceae) has been used traditionally in Ayurveda for the treatment of central nervous system disorders. 3,4-bis(3,4-dimethoxyphenyl)furan-2,5-dione (BDFD) was isolated from heart wood of Cedrus deodara and was shown to have antiepileptic and anxiolytic activity. Thus, the present study was aimed to explore its anti-depressant effect and to correlate the effect with serotonin and nor adrenaline levels of brain. Albino mice were used as experimental animal. Animals were divided in to three groups; vehicle control, imipramine (30 mg/kg i.p.), BDFD (100 mg/kg i.p.). Tail suspension test (TST) and forced swim test (FST) was performed to evaluate antidepressant effect of BDFD. BDFD (100 mg/kg, i.p.) showed a significant decrease in immobility time when subjected to FST whereas immobility time was not significantly altered in TST. BDFD treatment increased serotonin and noradrenaline levels in the brain which is indicative of BDFD having possible atypical antidepressant action.

Effect of permeation enhancers in the mucoadhesive buccal patches of salbutamol sulphate for unidirectional buccal drug delivery.

The purpose of this work was to study the effect of various permeation enhancers on the permeation of salbutamol sulphate (SS) buccal patches through buccal mucosa in order to improve the bioavailability by avoiding the first pass metabolism in the liver and possibly in the gut wall and also achieve a better therapeutic effect. The influence of various permeation enhancers, such as dimethyl sulfoxide (DMSO), linoleic acid (LA), isopropyl myristate (IPM) and oleic acid (OA) on the buccal absorption of SS from buccal patches containing different polymeric combinations such as hydroxypropyl methyl cellulose (HPMC), carbopol, polyvinyl alcohol (PVA), polyvinyl pyrollidone (PVP), sodium carboxymethyl cellulose (NaCMC), acid and water soluble chitosan (CHAS and CHWS) and Eudragit-L100 (EU-L100) was investigated. OA was the most efficient permeation enhancer increasing the flux greater than 8-fold compared with patches without permeation enhancer in HPMC based buccal patches when PEG-400 was used as the plasticizer. LA also exhibited a better permeation enhancing effect of over 4-fold in PVA and HPMC based buccal patches. In PVA based patches, both OA and LA were almost equally effective in improving the SS permeation irrespective of the plasticizer used. DMSO was more effective as a permeation enhancer in HPMC based patches when PG was the plasticizer. IPM showed maximum permeation enhancement of greater than 2-fold when PG was the plasticizer in HPMC based buccal patches.

Crystal structure of 4-amino-1-(4-methyl-benz-yl)pyridinium bromide.

The title mol-ecular salt, C13H15N2 (+)·Br(-), crystallized with two independent ion pairs (A and B) in the asymmetric unit. In the cations, the planes of the pyridine and benzene rings are inclined to one another by 79.32 (8) and 82.30 (10)° in ion pairs A and B, respectively. In the crystal, the anions and cations are connected by N-H⋯Br hydrogen bonds, forming a centrosymmetric tetra-mer-like unit enclosing an R 8 (4)(16) ring motif. These units are linked via C-H⋯Br hydrogen bonds, forming a three-dimensional network.

Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion.

Candesartan cilexetil (CC) is a newer class of angiotensin II receptor antagonist used for the treatment of hypertension. The solubility of the CC is very poor and its oral bioavailability is only 15%. The controlledrelease polar lipid microparticles of CC (formulations F1, F2, F3 and F4) were prepared using variable erodible lipophilic excipients like hydrogenated castor oil, stearic acid, cetostearyl alcohol and carnauba wax by fusion method. The particle sizes of polar lipid microparticles were less than 50 microns and they were irregular in shape. Drug content ranged between 98.96 ± 2.1 and 101.9 ± 1.6% were present in all the formulations. The formulation F3 showed better drug release throughout the study period in a controlled release manner. Moreover, the in vitro release showed that all the formulations were best fitted to Higuchi model. Accelerated stability studies indicated that there was no significant changes in the chemical and physical characteristics of the formulated drug product during initial and at the end of the study period. The FTIR and DSC studies showed that there was no interaction between the drug and lipophilic excipients and no polymorphic transitions in all formulations. The X-ray diffraction peak of solid dispersion indicated that the crystalline nature of CC disappeared and no new peaks could be observed, suggesting the absence of interaction between drug and excipients.

Antinociceptive and antiinflammatory activities and QSAR studies on 2-substituted-4,5-diphenyl-1H-imidazoles.

This paper describes the pharmacological evaluation pertaining to antinociceptive (hot plate and tail flick) and antiinflammatory (based on Carrageenan-induced paw oedema) activities, and QSAR studies on 2-substituted-4,5-diphenyl-1H-imidazoles. Compounds with phenyl substitution with -F, -Cl, -NH(2), -N(CH(3))(2), -OH and -OCH(3) at the p-position showed higher activity than the other substitutions in all the three studies. QSARs developed for the 60 and 120s hot plate data indicate that the models for both the cases not only fit the data very well (R(2)>0.9, R(adj)(2)>0.86), but also have very good predictive capability (q(2)>0.81). The descriptors used in the model relate to surface area, volume, dipole moment and ADME properties of the molecule. Good QSARs for the 60 and 120s tail flick data are developed. The models fit the data well (R(2)>0.8, R(adj)(2)>0.74), and in addition have good predictive capability (q(2)>0.66). Surface area, specifically polar surface area, HOMO and molecular connectivity index appear in the models. Very good QSAR model is developed for the antiinflammatory data (R(2)=0.86, R(adj)(2)=0.822 and q(2)=0.64) with aqueous solubility, number of hydrogen bond donor groups, surface area and principal moment of inertia as the molecular descriptors.

Effect of root extract of Aegle marmelos on dermal wound healing in rats.

The wound healing effect of methanolic extract of the root of aegle marmelos was evaluated in the form of an ointment with two different concentrations (5% and 10% w/w in simple ointment base) in excision wound model and incision wound model in rats. In both the concentrations, the extract ointment produced a significant response in both the wound types tested, as evidenced by its wound contracting ability, wound closure time and increase in the tensile strength. The results were also comparable to those of a standard drug nitrofurazone.