A chirality-sensitive approach to predict chemical transfer across the human placental barrier.

The placenta is a membrane that separates the fetus from the maternal circulation, and in addition to protecting the fetus, plays a key role in fetal growth and development. With increasing drug use in pregnancy, it is imperative that reliable models of estimating placental permeability and safety be established. In vitro methods and animal models such as rodent placenta are limited in application since the species-specific nature of the placenta prevents meaningful extrapolations to humans.

A-kinase anchoring proteins are enriched in the central pair microtubules of motile cilia in Chlamydomonas reinhardtii.

Cilia are microtubule-based sensory organelles present in a number of eukaryotic cells. Mutations in the genes encoding ciliary proteins cause ciliopathies in humans. A-kinase anchoring proteins (AKAPs) tether ciliary signaling proteins such as protein kinase A (PKA).

A novel thermoresponsive nano carrier matrix of hyaluronic acid, methotrexate and chitosan to target the cluster of differentiation 44 receptors in tumors.

Major challenges in current cancer chemotherapy include drug resistance, low efficacy and non-selectivity, resulting in undesirable side effects. In this study, we demonstrate a solution to these challenges that involves a dual targeting approach for tumors that overexpress CD44 receptors. The approach employs a nano-formulation (tHAC-MTX nano assembly), fabricated from hyaluronic acid (HA), the natural ligand for CD44, conjugated with methotrexate (MTX) and complexed with the thermoresponsive polymer 6-O-carboxymethylchitosan (6-OCMC) graft poly(N-isopropylacrylamide) [6-OCMC-g-PNIPAAm].

Natural Anticancer Agents: Their Therapeutic Potential, Challenges,s and Promising Outcomes.

Cancer, the second leading cause of death worldwide, is a major health problem. Chemotherapy, radiation therapy and surgery are current treatments for cancer. Most anticancer drugs have severe toxic effects and are required to be administered in cycles to reduce toxicity and prevent resistance.

How effective are ionization state-based QSPKR models at predicting pharmacokinetic parameters in humans?

Optimizing the pharmacokinetics (PK) of a drug candidate to support oral dosing is a key challenge in drug development. PK parameters are usually estimated from the concentration-time profile following intravenous administration; however, traditional methods are time-consuming and expensive. In recent years, quantitative structure-pharmacokinetic relationship (QSPKR), an in silico tool that aims to develop a mathematical relationship between the structure of a molecule and its PK properties, has emerged as a useful alternative to experimental testing.

Prediction of QcrB Inhibition as a Measure of Antitubercular Activity with Machine Learning Protocols.

It has always been a challenge to develop interventional therapies for . Over the years, several attempts at developing such therapies have hit a dead-end owing to rapid mutation rates of the tubercular bacilli and their ability to lay dormant for years. Recently, cytochrome complex (QcrB) has shown some promise as a novel target against the tubercular bacilli, with Q203 being the first molecule acting on this target.

A Review on Exploring the Opportunities of Polymer Drug Conjugated Systems for Targeted Cancer Treatment.

Polymeric drug conjugates (PDCs) for cancer therapy have been a hot research topic for the past three decades. Successful examples of PDC conjugates have demonstrated sustained drug release action with decreased systemic toxicity and enhanced tumor retention effect (EPR) via active as well as passive targeting mechanisms. Therefore, the PDC approach has now become a keystone of the drug delivery system for cancer and other diseases.

Amalgamation of comparative protein modeling with quantitative structure-retention relationship for prediction of the chromatographic behavior of peptides.

Peptide therapeutics plays a prominent role in medical practice. Both peptides and proteins have been used in several disease conditions like diabetes, cancer, bacterial infections etc. The optimization of a peptide library is a time consuming and expensive chore.

Identification of potential antileishmanial 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-ones, in vitro metabolic stability, cytotoxicity and molecular modeling studies.

We report the synthesis and in vitro evaluation of 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives against Leishmania donovani. Amongst the compound library synthesized, molecules 3d, 3f, 3h, 3i, 3l, and 3m demonstrated substantial dose-dependent killing of the promastigotes. Their IC values range from 55.

Novel Temperature Responsive Films Impregnated with Silver Nano Particles (Ag-NPs) as Potential Dressings for Wounds.

Silver nanoparticles have attracted wide interest in medicine on account of their antibacterial activity. We report in this paper, the antibacterial activity and biocompatibility of a temperature responsive topical film fabricated from pullulan-g-pNIPAM and impregnated with two different concentrations (15 ppm and 30 ppm) of silver nanoparticles (Ag-NPs). The release of silver from the film under the influence of temperature above the LCST has been studied and the in vitro release profile of the films has been compared with a marketed silver nano formulation, 'Meganano gel'.

Design, synthesis and SAR of antitubercular benzylpiperazine ureas.

N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule (I) with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC ~ 80 μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with (I), fifty-five analogs were synthesized and screened against Mtb.

A QSAR modeling approach for predicting myeloid antimicrobial peptides with high sequence similarity.

Microbial resistance to conventional antibiotics has led to a surge in antimicrobial peptide (AMP) rational design initiatives that rely heavily on algorithms with good prediction accuracy and sensitivity. We present a quantitative structure-activity relationship (QSAR) approach for predicting activity of cathelicidins, an AMP family with broad-spectrum activity. The best multiple linear regression model built against Escherichia coli ATCC 25922 could accurately predict activity of three rationally designed peptides CP, DP, and Mapcon, having high sequence similarity.

Novel p-Functionalized Chromen-4-on-3-yl Chalcones Bearing Astonishing Boronic Acid Moiety as MDM2 Inhibitor: Synthesis, Cytotoxic Evaluation and Simulation Studies.

Background: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines.

Objectives: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein.

Preferential Formulation of Second Generation Antipsychotic Asenapine as Inclusion Complex with Sulphobutylether-βCD (Captisol): In vitro and In vivo Evaluation.

Background: Asenapine is an anti-psychotic agent approved by the US-FDA for treatment of acute schizophrenia and manic or bipolar I disorder in adults. It is poorly absorbed when administered orally, hence exhibits poor oral bioavailability, which limits its use in clinical practice.

Objective: Enhancement in solubility of asenapine through complexation with three different cyclodextrins, viz.

Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity.

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile.

Novel thermoresponsive assemblies of co-grafted natural and synthetic polymers for water purification.

Water contamination and its purification are a global problem. The current approach to purify water is reduction of impurities to acceptable levels. One of the ways to achieve this is by use of water-soluble polymers that extract organic and metallic contaminants, from water.

Soluble curcumin amalgamated chitosan microspheres augmented drug delivery and cytotoxicity in colon cancer cells: In vitro and in vivo study.

In present investigation, initially curcumin was complexed with 2-HP-β-CD (curcumin-2-HP-β-CD-complex) in 1:1 ratio and later amalgamated with chitosan microspheres (curcumin-2-HP-β-CD-CMs) for selective delivery in colon only through oral route of administration. Various analytical, spectral and in-silico docking techniques revealed that the curcumin was deeply inserted in the 2-HP-β-CD cavity with apparent stability constant of 3.35×10M.

A Computational Model for Docking of Noncompetitive Neuraminidase Inhibitors and Probing their Binding Interactions with Neuraminidase of Influenza Virus H5N1.

Background: With cases of emergence of drug resistance to the current competitive inhibitors of neuraminidase (NA) such as oseltamivir and zanamavir, there is a present need for an alternative approach in the treatment of avian influenza. With this in view, some flavones and chalcones were designed based on quercetin, the most active naturally occurring noncompetitive inhibitor.

Objective: We attempt to understand the binding of quercetin to H5N1-NA, and synthetic analogs of quercetin namely flavones and its precursors the chalcones using computational tools.

Characterization of pioglitazone cyclodextrin complexes: Molecular modeling to in vivo evaluation.

Aims: The objective of present study was to study the influence of different β-cyclodextrin derivatives and different methods of complexation on aqueous solubility and consequent translation in in vivo performance of Pioglitazone (PE).

Material And Methods: Three cyclodextrins: β-cyclodextrin (BCD), hydroxypropyl-β-cyclodextrin (HPBCD) and Sulfobutylether-7-β-cyclodextrin (SBEBCD) were employed in preparation of 1:1 Pioglitazone complexes by three methods viz. co-grinding, kneading and co-evaporation.

Evaluation of risedronate as an antibiofilm agent.

Escherichia coli cra null mutants have been reported in the literature to be impaired in biofilm formation. To develop E. coli biofilm-inhibiting agents for prevention and control of adherent behaviour, analogues of a natural Cra ligand, fructose-1,6-bisphosphate, were identified based on two-dimensional similarity to the natural ligand.

Design, synthesis and evaluation of benzotriazole derivatives as novel antifungal agents.

Considering the need for discovery of new antifungal drugs with greater potency and broader spectrum of activity, a new series of 5-substituted benzotriazole derivatives were designed, through structure based design, as inhibitors of fungal cytochrome P450 lanosterol 14-α demethylase. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some benzotriazole derivatives were synthesized and characterized by IR, (1)H NMR and MS/MS.

Drug-DNA Interaction Studies of Acridone-Based Derivatives.

N10-alkylated 2-bromoacridones are a novel series of potent antitumor compounds. DNA binding studies of these compounds were carried out using spectrophotometric titrations, Circular dichroism (CD) measurements using Calf Thymus DNA (CT DNA). The binding constants were identified at a range of K=0.

In silico optimization of pharmacokinetic properties and receptor binding affinity simultaneously: a 'parallel progression approach to drug design' applied to β-blockers.

The present work exploits the potential of in silico approaches for minimizing attrition of leads in the later stages of drug development. We propose a theoretical approach, wherein 'parallel' information is generated to simultaneously optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of lead candidates. β-blockers, though in use for many years, have suboptimal PKs; hence are an ideal test series for the 'parallel progression approach'.

New horizons in antimalarial drug discovery in the last decade by chemoinformatic approaches.

Antimalarial drug discovery process is progressively carried out by a combination of innovation and knowledge based methods that include computational and experimental approaches to achieve potent leads. Among the various computational approaches, chemoinformatics plays a critical role in the discovery of new leads or drug candidates. Chemoinformatics provides researchers tools to derive information on substructures, chemical space, similarity and diversity.