Structure-guided screening of protein-protein interaction for the identification of Myc-Max heterodimer complex modulators.

De-regulation of oncogenic myelocytomatosis (c-Myc or Myc) transcription factor is one of the most common molecular anomalies encountered in human cancers, and it is typically linked to many aggressive malignancies including breast, lung, cervix, colon glioblastomas, and other haematological organs. The Myc belongs to the basic helix-loop-helix zipper protein family (bHLH-ZIP), and its dimerization with another principal interactor protein partner Myc-associated factor X (Max) is essentially required for cellular transformation, cell growth and proliferation, and transcriptional activation. Intermolecular interactions have been evaluated between hetero-dimer Myc-Max protein, which identified protein-protein interaction (PPI) specific modulators using highly précised molecular docking study followed by long-range interaction stability analyzed through molecular dynamic (MD) simulation. Moreover, ADME profile analyses have been estimated for screened hit compounds. MM-GBSA-based binding free energy (ΔG) estimations have been performed for all screened hit compounds obtained from multi-step molecular docking-based virtual screening technique. According to the employed various rigorous multi-chemometric techniques, four identified inhibitors/modulators appear to have a considerable number of intermolecular contacts with hotspot residues in the hetero-dimer interface region of the Myc-Max PPI complex. However, identified hit compounds might need further structural optimization or extensive biophysical analyses for better understanding of the molecular mechanism for exhibiting the Myc-Max PPI interface binding stability.Communicated by Ramaswamy H. Sarma.

ROCK Inhibitors as an Alternative Therapy for Corneal Grafting: A Systematic Review.

Currently, corneal blindness is affecting >10 million individuals worldwide, and there is a significant unmet medical need because only 1.5% of transplantation needs are met globally due to a lack of high-quality grafts. In light of this global health disaster, researchers are developing corneal substitutes that can resemble the human cornea in vivo and replace human donor tissue. Thus, this review examines ROCK (Rho-associated coiled-coil containing protein kinases) inhibitors as a potential corneal wound-healing (CWH) therapy by reviewing the existing clinical and nonclinical findings. The systematic review was done from PubMed, Scopus, Web of Science, and Google Scholar for CWH, corneal injury, corneal endothelial wound healing, ROCK inhibitors, Fasudil, Netarsudil, Ripasudil, Y-27632, clinical trial, clinical study, case series, case reports, preclinical study, in vivo, and in vitro studies. After removing duplicates, all downloaded articles were examined. The literature search included the data till January 2023. This review summarized the results of ROCK inhibitors in clinical and preclinical trials. In a clinical trial, various ROCK inhibitors improved CWH in individuals with open-angle glaucoma, cataract, iris cyst, ocular hypertension, and other ocular diseases. ROCK inhibitors also improved ocular wound healing by increasing cell adhesion, migration, and proliferation in vitro and in vivo. ROCK inhibitors have antifibrotic, antiangiogenic, anti-inflammatory, and antiapoptotic characteristics in CWH, according to the existing research. ROCK inhibitors were effective topical treatments for corneal infections. Ripasudil, Y-27632, H-1152, Y-39983, and AMA0526 are a few new ROCK inhibitors that may help CWH and replace human donor tissue.

Exploring allosteric hits of the NS2B-NS3 protease of DENV2 by structure-guided screening.

Despite the rising number of cases and increasing global disease burden, there is no definitive therapy against dengue to date, which necessitates the urgent discovery of inhibitors against the virus. The NS2B-NS3 serine protease of the dengue virus (DENV) catalyses polyprotein cleavage and is a potential target for drug discovery. The protease possesses a potentially druggable allosteric site, and the binding of inhibitors to this site locks the protease in an inactive conformation. The allosteric site is a potential druggable target for drug discovery against flaviviruses. This study aimed to identify serotype-specific hits against the allosteric site in the NS2B-NS3 protease of DENV serotype 2 (DENV2) from the Enamine, Selleck, and ChemDiv antiviral libraries. The prepared libraries were screened using a redocking and rescoring-based strategy with Glide SP and Glide XP, and the hitlist was initially screened by comparing their docking scores with that of reported allosteric inhibitors, myricetin and curcumin. The hitlist was subsequently screened by comparing the molecular mechanics with generalised Born and surface area solvation (MM-GBSA) energy with that of the standards. Ten hits were finally selected by virtual screening, and the stability of the hit-receptor complexes was determined with 100 ns molecular dynamics (MD) simulations in an explicit solvent. Trajectory visualisation and analyses of the RMSD and RMSF values revealed that three hits, including two catechins, remained stably bound to the allosteric binding site throughout the production run. Hit-receptor interaction analyses revealed that the hits formed highly stable interactions with Glu 88, Trp 89, Leu 149, Ile 165, and Asn 167, and MM-GBSA energy analysis revealed that the three hits had high binding affinity to the allosteric site. The findings obtained herein can aid in identifying novel serotype-specific inhibitors of DENV protease in future.

Exploring Potential Non-steroidal Aromatase Inhibitors for Therapeutic Application against Estrogen-dependent Breast Cancer.

BACKGROUND: Breast cancer is one of the most commonly diagnosed cancer types among women worldwide. Cytochrome P450 aromatase (CYP19A1) is an enzyme in vertebrates that selectively catalyzes the biosynthesis of estrogens from androgenic precursors. Researchers have increasingly focused on developing non-steroidal aromatase inhibitors (NSAIs) for their potential clinical use, avoiding steroidal side effects. OBJECTIVES: The objective of the present work is to search for potential lead compounds from the ZINC database through various in silico approaches. METHODS: In the present study, compounds from the ZINC database were initially screened through receptor independent-based pharmacophore virtual screening. These screened molecules were subjected to several assessments, such as Lipinski rule of 5, SMART filtration, ADME prediction using SwissADME and lead optimization. Molecular docking was further applied to study the interaction of the filtered compounds with the active site of aromatase. Finally, the obtained hit compounds, consequently represented to be ideal lead candidates, were escalated to the MD simulations. RESULTS: The results indicated that the lead compounds might be potential anti-aromatase drug candidate. CONCLUSION: The findings provided a valuable approach in developing novel anti-aromatase inhibitors for the treatment of ER+ breast cancer.

Search for potentially biased epidermal growth factor receptor (EGFR) inhibitors through pharmacophore modelling, molecular docking, and molecular dynamics (MD) simulation approaches.

Epidermal growth factor receptor (EGFR), being one of the most crucial receptor in cancer therapy, has been selected as a potential target for the present study. Ligand-based pharmacophore model (n = 30, R2=0.93 with root mean square deviation = 1.14, ΔCost = 144.27 and configuration cost = 21) was developed and validated with Fischer's randomisation (at 95% confidence), test set (n = 225, R2 pred = 0.81), external data set (n = 13, R2 pred = 0.95) and decoy set (n = 70), further the model has been used to search for novel EGFR inhibitors. The validated model was used for virtual screening of zinc database. A pool of 115,948 candidate molecules was screened through the model. Subsequently, molecules having predicted IC50<0.2 µM were selected for screening through drug-like properties filter. Based on pharmacokinetic profile (ADMET study), Lipinski's rule of five and Veber's rule, 62 molecules were shortlisted for molecular docking. Using consensus docking, five hit molecules were selected, which were further considered for molecular dynamics simulation. Additionally MM-GBSA analysis was carried which showed that affinity of hits towards the receptor of three compound mainly ZINC305, ZINC131796 and ZINC131785 were similar to the standard vanedtinib. The simulation, performed for 100 ns, revealed that two hit molecules, namely ZINC305 and ZINC131785, showing potential interactions at the ligand-binding domain of EGFR protein with good ligand-protein stability. Communicated by Ramaswamy H. Sarma.

Quercetin: a silent retarder of fatty acid oxidation in breast cancer metastasis through steering of mitochondrial CPT1.

BACKGROUND: Recent evidence confirmed that the maximum energy in metastatic breast cancer progression is supplied by fatty acid oxidation (FAO) governed by a rate-limiting enzyme, carnitine palmitoyltransferase 1 (CPT1). Therefore, the active limitation of FAO could be an emerging aspect to inhibit breast cancer progression. Herein, for the first time, we have introduced quercetin (QT) from a non-dietary source (Mikania micrantha Kunth) to limit the FAO in triple-negative breast cancer cells (TNBC) through an active targeting of CPT1. METHODS: Molecular quantification of QT was confirmed through high-performance thin-layer chromatography (HPTLC). Computational docking analyses predicted the binding affinity of QT to CPT1. Cell-based seahorse energy efflux investigated the mitochondrial respiration rate, glycolytic function and ATP production rate. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) investigated the FAO-associated gene expression. Matrigel cell invasion and fluorescence-activated cell sorting analyses investigated anti-metastatic and apoptotic cell death induction activities, respectively. In vivo antitumor activities were checked using the female breast cancer mice (BALB/c) model. RESULTS: QT resulted in a significant reduction in the intracellular mitochondrial respiration and glycolytic function, limiting extensive ATP production. In turn, QT elevated the reactive oxygen species (ROS) and depleted antioxidant levels to induce anti-metastatic and cell apoptosis activities. qRT-PCR resulted in active healing of altered FAO-associated gene expression which was well predicted through the successful in silico molecular binding potentiality of QT to CPT1. Subsequently, QT has shown excellent in vivo antitumor activities through the altered lipid profile and oxidative stress-healing capabilities. CONCLUSIONS: All the obtained data significantly grounded the fact that QT could be a promising metabolism-targeted breast cancer therapeutic.

Exploring CIP2A modulators using multiple molecular modeling approaches.

Like other human oncoproteins, Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) exerts cancer promoting function through interaction with other partner proteins, such as MYC and Protein Phosphatase 2A (PP2A). CIP2A regulates several MYC-independent and/or dependent gene expression programs. Broadly, CIP2A can inhibit PP2A, and especially it has been shown to inhibit MYC-associated PP2A, precisely to increase MYC stability and function. Availability of crystal structure has broached the research focus to develop new therapeutics targeting CIP2A. In the present study, structural information of the protein has been used for identification of modulators for homo-dimer CIP2A using advanced structure-based drug design approaches. The compound library, 'Maybridge Screening Collection' database (∼62,000 compounds) has been virtually screened to find out potent modulators for CIP2A. Identification of hotspot region on CIP2A protein-protein interaction interface has been performed using three different tools (HotPoint, SiteMap and icmPocketFinder). Thereafter, molecular docking (Extra Precision and Induced Fit Docking), and long range molecular dynamics simulation analysis, and ADME profile analysis have been carried out for screening purposes. Calculations of MM-PBSA based binding free energy (ΔG), and Density Functional Theory for quantum chemical simulations have been carried out for the hit compounds obtained through multi-step molecular docking based virtual screening technique. The multi-chemometric studies suggested that hit modulators have formed significant numbers of molecular interactions with hotspot residues in the homo-dimer interface region, which enable to hold CIP2A binding stability. Compounds with average ΔG values (ranging -3.4 x 10-2 to -1.1 x 10-2 KJ/mol) signifying promising CIP2A modulators.Communicated by Ramaswamy H. Sarma.

Structure-based identification of galectin-1 selective modulators in dietary food polyphenols: a pharmacoinformatics approach.

In this study, a set of dietary polyphenols was comprehensively studied for the selective identification of the potential inhibitors/modulators for galectin-1. Galectin-1 is a potent prognostic indicator of tumor progression and a highly regarded therapeutic target for various pathological conditions. This indicator is composed of a highly conserved carbohydrate recognition domain (CRD) that accounts for the binding affinity of ß-galactosides. Although some small molecules have been identified as galectin-1 inhibitors/modulators, there are limited studies on the identification of novel compounds against this attractive therapeutic target. The extensive computational techniques include potential drug binding site recognition on galectin-1, binding affinity predictions of ~ 500 polyphenols, molecular docking, and dynamic simulations of galectin-1 with selective dietary polyphenol modulators, followed by the estimation of binding free energy for the identification of dietary polyphenol-based galectin-1 modulators. Initially, a deep neural network-based algorithm was utilized for the prediction of the druggable binding site and binding affinity. Thereafter, the intermolecular interactions of the polyphenol compounds with galectin-1 were critically explored through the extra-precision docking technique. Further, the stability of the interaction was evaluated through the conventional atomistic 100 ns dynamic simulation study. The docking analyses indicated the high interaction affinity of different amino acids at the CRD region of galectin-1 with the proposed five polyphenols. Strong and consistent interaction stability was suggested from the simulation trajectories of the selected dietary polyphenol under the dynamic conditions. Also, the conserved residue (His44, Asn46, Arg48, Val59, Asn61, Trp68, Glu71, and Arg73) associations suggest high affinity and selectivity of polyphenols toward galectin-1 protein.

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches.

The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.

Assessment of toxicological consequences upon acute inhalation exposure to chemically improvised nonlethal riot control combinational formulation (NCF) containing oleoresin capsicum and skatole.

Sensory irritation is an acute adverse effect leading to temporary disability posed by riot control agents in various deployable forms are utilized by defense personal in violent mob attacks but their irreversible toxic effects and risk assessment have been a matter of concern. These intimidating risks of available riot control agents have led to exploring the pulmonary toxicity profile of the oil in water emulsion formulation developed for vicious crowd controls containing an irritant oleoresin capsicum, a malodorant (skatole), and a commercial dye, followed by characterization using standard methods. Nonlethal riot control combinational formulation (NCF) has been aimed to be the best possible low-lethal alternative for riot control measures. In this study, 30 min of acute inhalation exposure of NCF was given to Wistar rats and various respiratory parameters like lung dynamics, bronchoalveolar lavage fluid (BALF) cytological assays, pro-inflammatory cytokines estimation, antioxidant activity, collagen accumulation, cytotoxicity, in vivo lung imaging, western blot, histology of lung tissue, etc. were investigated to validate its potentiality and rate of irritation reversibility as nonlethal agents. An exaggerated physiological change like sensory irritation, changes in lung functional variables, increased pro-inflammatory cytokines, etc. were noticed initially without airway obstruction as the expression of nociceptive TRPV1 protein did not alter the physiological regulation of protective proteins like Nrf2 and HO-1 and also no abnormality was found in lung tissue architecture. In conclusion, it can be stated that this formulation can be explored as a nonlethal riot control agent intending to generate discomfort but with early reversibility of sensory irritation and no recurrence of toxicity.

Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.

Simultaneous Pharmacokinetics Estimation of Nateglinide and Pioglitazone by RP-HPLC: Computational Study to Unlock the Synergism.

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 µm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.

Carnosic Acid Attenuates Cadmium Induced Nephrotoxicity by Inhibiting Oxidative Stress, Promoting Nrf2/HO-1 Signalling and Impairing TGF-ß1/Smad/Collagen IV Signalling.

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-ß1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05-0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-ß1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity.

Synthesis, anticancer activity, structure-activity relationship and binding mode of interaction studies of substituted pentanoic acids.

Aim: Simultaneous inhibition of MMP-2 and HDAC8 may be an effective strategy to target cancer. Methodology: In continuation of our earlier efforts, a series of substituted pentanoic acids (1-18) were synthesized and checked for their biological activity along with some earlier reported compounds (19-35). Results: Compounds 18 and 31 were found to induce apoptosis effectively in a dose-dependent fashion in Jurkat-E6.1 cell line. They reduced the expression of both MMP-2 and HDAC8 effectively. 31 also produced prominent intensity of fluorescence to bring nick in Jurkat-E6.1 cells. 31 also showed cellular arrest in sub-G0 phase. Conclusion: Such compounds may be useful to battle against cancer.

Rosmarinic Acid Attenuates Cadmium-Induced Nephrotoxicity via Inhibition of Oxidative Stress, Apoptosis, Inflammation and Fibrosis.

The present investigation was executed to reveal the protective mechanism of rosmarinic acid (RA) against cadmium (Cd)-induced nephrotoxicity. RA exhibited a concentration-dependent anti-apoptotic effect against CdCl2 in isolated mouse proximal tubular epithelial cells. Cd treatment significantly (p < 0.01) imparted oxidative stress to the renal cells via excessive ROS production, triggering NO level, NADPH oxidase activation, and impairment of cellular redox defense system. Cd-mediated oxidative stress significantly (p < 0.01) endorsed apoptosis to the murine kidney cells by triggering NF-κB/PKC-δ/TNFR2 activation. In addition, CdCl2 induced renal fibrosis by triggering TGF-ß1/SMAD3/α-SMA/collagen signaling within renal cells. On the other hand, RA significantly (p < 0.05-0.01) attenuated Cd-provoked oxidative stress and associated pathological signal transduction in murine renal cells. RA treatment also could significantly (p < 0.05-0.01) reciprocate Cd-mediated pathological changes in blood and urine parameters in mice. In addition, histological data supported the pharmacological findings. In silico chemometric analyses predicted the possible interactions between RA and different signal proteins and anticipated drug-likeness characteristics of RA. Hence, RA can potentially be applied as a therapeutic agent to treat Cd-mediated nephrotoxicity in future.

Supramolecular Assembly of Amino Acid Based Cationic Polymer for Efficient Gene Transfection Efficiency in Triple Negative Breast Cancer.

The success of gene therapy is enormously dependent on an efficient gene carrier, and in this context, cationic polymers still continue to play a major role particularly with respect to the safety issue compared to viral vectors. Developing an efficient gene carrier system having promising gene transfection efficiency with low toxicity is the foremost impediment associated with a nonviral carrier. Here, we explored amino acid based biocompatible polymers synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization where glycine (Gly), leucine (Leu), and phenyl alanine (Phe) amino acids were used as the pendent groups of the polymeric brushes. The presence of both a hydrophobic group (long chain aliphatic group associated with the RAFT agent) and hydrophilic amino groups was associated with the supramolecular assembly of the polymeric chain having hydrodynamic sizes within the range of 150-300 nm with a positive zeta potential of 30 ± 5 mV. All polymers showed very low toxicity and possessed >80% cell viability even at a very high concentration of 1000 µg/mL against both normal and cancerous cells. In addition to this, the polymers also showed excellent blood compatibility, and negligible hemolysis was observed at the concentration of 500 µg/mL. All polymers showed efficient DNA complexation capability as well as excellent protection of DNA against highly negatively charged surfactant and enzymatic digestion, although the efficiency was dependent on the N/P ratio of polymer/DNA complexes. Interestingly, the phenyl alanine moiety containing polymer brush P(HEMA-Phe-NH2) showed a hexagonal shaped nanoparticle after complexation with pDNA and consequently showed higher cellular uptake, resulting in a higher transfection efficiency in a triple negative breast cancer cell, the MDA-MB-231 cell. Therefore, the synthesized polymer containing an amino acid pendent group, especially the phenyl alanine moiety, may be a promising nonviral gene carrier system in gene therapy application in the future.

Discovery of nano-piperolactam A: A nonsteroidal contraceptive lead acting through down-regulation of interleukins.

Elevated serum interleukins (IL-6, IL-1ß) over baseline concentration help in blastocyst adhesion to the uterine endometrium in the early phase of pregnancy. A nano PLA (Piperolactam A)-HPBCD (2-hydroxy-propyl-ß-cyclodextrin) inclusion complex was developed as an interleukin down-regulator that exhibited 100% anti-implantation activity in rodents at a dose as low as 2.5-5.0 mg/kg. On metabolomics study, among major glyco-lipo-protein metabolites, only serum low-density lipoprotein (LDL) or very low-density lipoprotein (VLDL) levels revealed alteration by the formulation. Administration of PLA-HPBCD did not cause changes in serum estrogen and progesterone levels. However, IL-6 and IL-1ß failed to increase post PLA-HPBCD administration; hence, it is assumed to be the mode of the drug's abortifacient action. In addition, absence of signs of either acute or chronic toxicity suggests the formulation was considerably non-toxic. Therefore, the nano-PLA conjugate promises as a non-steroidal contraceptive lead apart from ormeloxifene, the only non-steroidal anti-fertility agent currently available globally.

Synthesis of Novel tricyclic pyrazolo(1,4)oxathiinopyrazines and Evaluation of Their Competency Towards the Inhibition of Lactate Dehydrogenase Activity-Inhibition of LDH Activity.

We have evaluated the LDH inhibitory property of novel pyrazolo[4',3':5,6][1,4]oxathiino[2,3-b]pyrazine derivatives which have been synthesized from easily available starting materials through a one-pot protocol that offers the use of elemental sulfur as the sulfur source. These newly synthesized compounds may aid to drug development for neoplastic and non-neoplastic diseases characterized by increased glucose metabolism. Additionally, they may act as suitable starting materials which can be further structurally modified for the development of new LDH inhibitors with higher efficacy and specificity.

Combating breast cancer with non-steroidal aromatase inhibitors (NSAIs): Understanding the chemico-biological interactions through comparative SAR/QSAR study.

It is a challenging task to design target-specific and less toxic non-steroidal aromatase inhibitors (NSAIs) though the modeling studies for designing anti-aromatase molecules have been continuing for more than two decades to fight the dreaded estrogen-dependent breast cancer. In this article, different validated QSAR models are developed and analyzed to understand important physicochemical and structural parameters modulating the aromatase inhibitory activity of NSAIs. Physicochemical properties such as molar refractivity and dipole moment are found to be the most important parameters for controlling aromatase inhibition. This indicates the characteristic of bulky, complex and steric properties as well as, the flexibility of molecules is playing pivotal roles for aromatase inhibition. In many cases, hydrophobicity also plays important contribution. Regarding the structural point of view, some important indicator parameters are also found to be important for aromatase inhibitory activity. Though azole function is playing a crucial role by coordinating the heme moiety of the aromatase enzyme, the imidazole or the imidazolylmethyl ring systems may be better NSAIs than triazole, tetrazole or other azoles. The 4-pyridylmethyl group containing compounds are also found to be better NSAIs. The QSAR study, in a nutshell, provides a detailed understanding of the effectivity of NSAIs which is dependent mainly on the shape and size as well as the steric features of molecules and the heme-coordinator azole functions. These findings may open up a new horizon for designing new potential NSAIs that can be effective to reduce the mortality rate of breast cancer in future.

Fabrication of ß-cyclodextrin-mediated single bimolecular inclusion complex: characterization, molecular docking, in-vitro release and bioavailability studies for gefitinib and simvastatin conjugate.

OBJECTIVES: Introduction of multiple molecules in a single inclusion complex, albeit cheaper, lacks conclusive attempts in earlier drug delivery reports. This manuscript emphasizes simultaneous incorporation of two anticancer drugs, gefitinib (G) and simvastatin (S), in a single molecule of ß-cyclodextrin for the first time to achieve effective drug delivery. METHODS: The inclusion complex (GSBCD) was prepared by cosolvent evaporation technique using ß-cyclodextrin (BCD) as carrier. Characterization of GSBDC was performed by Fourier transform infrared spectroscopy, COSY, differential scanning calorimetry, X-ray diffraction and dynamic light scattering analyses, which were ascribed to the complex formation inside BCD cavity, micronization of drugs and conversion to amorphous state. KEY FINDINGS: The complex revealed entrapment of G and S in 3 ± 0.48: 2 ± 0.19 molar ratio and showed more than 3.5 and 10 fold increase in drug release in in vitro and in vivo, respectively. Docking and COSY studies revealed molecular alignment into BCD central cavity that been achieved via hydrogen bonding between certain groups of the ligands (G and S) and the polar heads of BCD. Partial incorporation of the molecular backbone inside inclusion complex suggests superficial contact with the solvent indicating slow steady release kinetics. CONCLUSIONS: This approach of forming inclusion complex with multiple molecules within a single cavity can be a landmark for further studies in drug delivery.