Usman Sayeed

Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier

Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included.

Elucidation of Antiangiogenic Potential of Vitexin Obtained from Cucumis sativus Targeting Hsp90 Protein: A Novel Multipathway Targeted Approach to Restrain Angiogenic Phenomena

BACKGROUND Angiogenesis involves the process of sprouting of microvessels from preexisting microvasculature and is held responsible for the growth, malignancy and metastasis of cancer. Heat shock protein Hsp90 has been proven responsible for indirectly inducing multiple pathways leading to angiogenesis and metastasis in cancer. Recent researches shift towards proposing novel phytochemicals as possible antiangiogenic agents. OBJECTIVE The study aims towards Virtual screening of compounds from Cucurbitaceae family and their Druglikeliness and PreADMET filtering in search of potent lead as Vitexin, targeting Hsp90 and hence restraining angiogenesis. MATERIALS AND METHODS Structures of phytochemicals from Cucurbitaceae family were retrieved from PubChem database and were converted into suitable 3-D structures. The target protein, Hsp90 was retrieved from RCSB Protein Data Bank. Phytochemicals of Cucurbitaceae family were filtered through enumerated Lipinskis rule of five and ADMET toxicity profiling and the filtered compounds were further taken forward for molecular docking analysis and interaction studies using AutoDock Tools 4.0. RESULTS The docking results revealed Vitexin, a prominent glycosylated natural flavonoid, showing promising inhibitory potential against Hsp90 with binding energy of -8.80 kcal/mole and Ki 353.24 nM as compared to its known inhibitor Ganetespib having binding energy of -7.33 kcal/mole and Ki 4260 nM. Vitexin also exhibits better drug having properties with satisfactory ADMET profiling in relation to Ganetespib. CONCLUSION The result proposes Vitexin to hold prominent antiangiogenic potential surpassing different in silico parameters and thus expected to be a multi-targeted novel antiangiogenic lead.

An Immuno-informatics driven Epitope study from the molecular interaction of JEV non-structural (NS) proteins with Ribophorin (RPN)

Japanese encephalitis (JE) is an acute viral infection of the central nervous system where the JE virus infects the lumen of the endoplasmic reticulum (ER) and rapidly accumulates substantial amount of seven different nonstructural proteins (NS). These NS proteins tend to bind on a glycoprotein receptor, ribophorin (RPN) resulting in the malfunctioning of ER in host cells, subsequently triggering an unfolded protein response. Therefore, it is of interest to predict the best possible antigenic determinants in the NS protein capable of eliciting immune response as a strategy to combat JE. Hence, it is our interest to explore the most potent NS protein among all showing the best possible molecular interaction with the RPN receptor present on ER. However, the structures of these NS protein and RPN are currently unknown. Thus, we modeled their structures using the established homology modeling techniques in the MODELLER 9v10 software. The molecular docking of NS proteins with RPN was subsequently completed using the Discovery Studio 2.5 software suite. The docked conformations of RPN with NS were further analyzed and its graphical interpretations were presented for identifying the most potential NS protein for efficient epitope activity. Further, the B cell epitopes were mapped using BCPred and the predicted epitope regions are documented. The data presented in this report provides useful insights towards the design and development of potential epitopes to generate a vaccine candidate against JEV.

Molecular Interaction and Computational Analytical Studies of Pinocembrin for its Antiangiogenic Potential Targeting VEGFR-2: A Persuader of Metastasis

BACKGROUND Designing a novel antagonist against VEGFR-2 is being applied currently to inhibit cancer growth and metastasis. Because of the unexpected side effects incurred by the contemporary anticancer medications, the focus has been laid towards identifying natural compounds that might carry the potential to inhibit tumor progression. VEGR-2 remains an important target for anticancer drug development as it is the master regulator of vascular growth. OBJECTIVE The study focuses on virtual screening of compounds from plants of Asteraceae family that bears antiangiogenic potential and thus, inhibiting VEGFR-2 using a computational approach. MATERIALS AND METHODS Structures of phytochemicals were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, VEGFR-2 was retrieved from RCSB PDB. Lipinskis rule and ADMET toxicity profiling were carried out on the phytochemicals of the Asteraceae family and the filtered compounds were further promoted for molecular docking and MD simulation analysis. The study extends towards the SOM analysis of Pinocembrin to predict the possible toxic and non-toxic in vivo metabolites via in silico tools (Xenosite Web and PASS online server). RESULTS The docking results revealed promising inhibitory potential of Pinocembrin against VEGFR-2 with binding energy of -8.50 kcal/mole as compared to its known inhibitors Sorafenib and YLT192 having binding energy of -6.49 kcal/mole and -8.02 kcal/mol respectively. Further, molecular dynamics (MD) simulations for 10ns were conducted for optimization, flexibility prediction, and determination of folded VEGFR-2 stability. The Hsp90-Pinocembrin complex was found to be quite stable with RMSD value of 0.2nm. Pinocembrin was found to be metabolically stable undergoing phase I metabolism with non-toxic metabolites compared to the standard drug Sorafenib and YLT192. CONCLUSION Obtained results propose Pinocembrin as a multi-targeted novel lead compound that bears outstanding antiangiogenic potential against VEGFR-2.

Cancer Nanotechnology - An Excursion on Drug Delivery Systems

BACKGROUND Nanotechnology pictures a breakthrough in the domain of cancer therapy owing to its novel properties and functions. This technology is quite amendable as it allows the scientists to engineer drug nanoparticles of dimensions 10nm - 500nm permitting them to pass via leaky vasculature of tumorigenic microenvironment with higher specificity, reduced cytotoxicity and effective release without any after effects. The central part of the review zooms onto the role of nanoparticles and their targeted delivery for the cure of cancer. METHODS The novel and various versatile nanoparticle platforms viz. polymeric (drug-conjugates, micelles, dendrimers), Lipid-based (liposomes, solid nanoparticle, nanostructured lipid carrier, lipid-polymer hybrid), and stimuli-sensitive (thermoresponsive, ultrasound, pH-responsive, hydrogel) etc. have been designed for a persistent, précised nanodrug delivery and the co-delivery of collegial drug conjugates leading to the formation of safer release of myriad of drugs for cancer chemoprevention. RESULTS The review concerns about tracing and detailing the drug delivery systems of cancer nanotechnology. CONCLUSION Nanotechnology is bestowed with the design, depiction, fabrication, and application of nanostructures, and devices with their controlled delivery together with the imaging of the selected target site and drug release at the specific site of action.

Carcinogenic Toxicity of Cigarette Smoke: A Computational Enzymatic Interaction and DNA Repair Pathways

We have performed the interaction analysis of cigarette smoke carcinogens with the enzymes involved in DNA repair mechanisms. Cigarette smoke’s derivatives like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are well known carcinogens. The binding efficiency of carcinogens with enzymes obtained from docking methods were ranging from +36.96 to −7.47 kcal/mol. Binding efficiency was characterized for the enzymes sharing equivalent or better interaction as compared to positive control. Also we have analyzed the interaction pattern of NNK and NNAL with DNA. The present study suggests that NNK and NNAL may alter the DNA repair machinery that could initiate the progression of tumor leading to cancer. Computational method explores the toxicological characteristics of these enzymes and also opening an opportunity for researchers.

MHC binding peptides for designing of vaccines against Japanese encephalitis virus: A computational approach

Japanese encephalitis (JE), a viral disease has seen a drastic and fatal enlargement in the northern states of India in the current decade. The better and exact cure for the disease is still in waiting. For the cause an in silico strategy in the development of the peptide vaccine has been taken here for the study. A computational approach to find out the Major Histocompatibility Complex (MHC) binding peptide has been implemented. The prediction analysis identified MHC class I (using propred I) and MHC class II (using propred) binding peptides at an expectable percent predicted IC (50) threshold values. These predicted Human leukocyte antigen [HLA] allele binding peptides were further analyzed for potential conserved region using an Immune Epitope Database and Analysis Resource (IEDB). This analysis shows that HLA-DRB1*0101, HLA-DRB3*0101, HLA-DRB1*0401, HLA-DRB1*0102 and HLA-DRB1*07:01% of class II (in genotype 2) and HLA-A*0101, HLA-A*02, HLA-A*0301, HLA-A*2402, HLA-B*0702 and HLA-B*4402% of HLA I (in genotype 3) bound peptides are conserved. The predicted peptides MHC class I are ILDSNGDIIGLY, FVMDEAHFTDPA, KTRKILPQIIK, RLMSPNRVPNYNLF, APTRVVAAEMAEAL, YENVFHTLW and MHC class II molecule are TTGVYRIMARGILGT, NYNLFVMDEAHFTDP, AAAIFMTATPPGTTD, GDTTTGVYRIMARGI and FGEVGAVSL found to be top ranking with potential super antigenic property by binding to all HLA. Out of these the predicted peptide FVMDEAHFTDPA for allele HLA-A*02:01 in MHC class I and NYNLFVMDEAHFTDP for allele HLA-DRB3*01:01 in MHC class II was observed to be most potent and can be further proposed as a significant vaccine in the process. The reported results revealed that the immune-informatics techniques implemented in the development of small size peptide is useful in the development of vaccines against the Japanese encephalitis virus (JEV).

Identification of potential leads against 4-hydroxytetrahydrodipicolinate synthase from Mycobacterium tuberculosis

4-hydroxy-tetrahydrodipicolinate synthase (DHDPS) is an important enzyme needed for the biosynthesis of lysine and many more key metabolites in Mycobacterium tuberculosis (Mtb). Inhibition of DHDPS is supposed to a promising therapeutic target due to its specific role in sporulation, cross-linking of the peptidiglycan polymers and biosynthesis of amino acids. In this work, a known inhibitor-based similarity search was carried out against a natural products database (Super Natural II) towards identification of more potent phyto-inhibitors. Molecular interaction studies were accomplished using three different tools to understand and establish the participation of active site residues as the key players in stabilizing the binding mode of ligands and target protein. The best phyto-compound deduced on the basis of binding affinity was further used as a template to make similarity scan across the PubChem Compound database (score > = 80 %) to get more divesred leads. In this search 5098 hits were obtained that further reduced to 262 after drug-likeness filtration. These phytochemicallike compounds were docked at the active site of DHDPS.Then, those hits selected from docking analysis that showing stronger binding and forming maximum H-bonds with the active site residues (Thr54, Thr55, Tyr143, Arg148 and Lys171). Finally, we predicted one phytochemical compound (SN00003544), two PubChem-compounds (CID41032023, CID54025334) akin to phytochemical molecule showing better interactions in comaprison of known inhibitors of target protein.These findings might be further useful to gain the structural insight into the designing of novel leads against DapA family.