Arpita Yadav

Self-Assembled Surfactant Cyclic Peptide Nanostructures as Stabilizing Agents

A number of cyclic peptides including [FR]4, [FK]4, [WR]4, [CR]4, [AK]4, and [WK]n (n = 3-5) containing L-amino acids were produced using solid-phase peptide synthesis. We hypothesized that an optimal balance of hydrophobicity and charge could generate self-assembled nanostructures in aqueous solution by intramolecular and/or intermolecular interactions. Among all the designed peptides, [WR]n (n = 3-5) generated self-assembled vesicle-like nanostructures at room temperature as shown by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and/or dynamic light scattering (DLS). This class of peptides represents the first report of surfactant-like cyclic peptides that self-assemble into nanostructures. A plausible mechanistic insight into the self-assembly of [WR]5 was obtained by molecular modeling studies. Modified [WR]5 analogues, such as [WMeR]5, [WR(Me)2]5, [WMeR(Me)2]5, and [WdR]5, exhibited different morphologies to [WR]5 as shown by TEM observations. [WR]5 exhibited a significant stabilizing effect for generated silver nanoparticles and glyceraldehyde-3-phosphate dehydrogenase activity. These studies established a new class of surfactant-like cyclic peptides that self-assembled into nanostructures and could have potential applications for the stabilization of silver nanoparticles and protein biomolecules.

Lead compound design for TPR/COX dual inhibition

AbstractThe modes of action of TxA2 antagonists and COX-2 inhibitors were studied utilizing flexible ligand docking with postdocking minimization and ab initio interaction energy calculations. The resulting increased understanding of their binding interactions led to the design of a lead compound with chemical moieties that allowed efficient binding to both the thromboxane receptor and the COX-2 enzyme. This compound is derived from allicin, a natural component of garlic, and is a good starting point for the development of anti-inflammatory drugs with fewer side effects or improved cardiovascular drugs. FigureLead compound design for TPR/COX dual inhibition

Amphiphilic Triazolyl Peptides: Synthesis and Evaluation as Nanostructures

A new class of amphiphilic triazolyl peptides was designed and synthesized from peptide-based building blocks containing alkyne and azide functional groups namely linear (W(pG))3, cyclic[W(pG)]3, and Ac-K(N3)R-NH2, where W, R, K, and pG represent tryptophan, arginine, lysine, and propargylglycine residues, respectively. The linear (W(pG))3 and cyclic [W(pG)]3 peptides containing alkyne residues were conjugated with Ac-K(N3)R-NH2 functionalized with azide group through click chemistry in the presence of CuSO4.5H2O, Cu (powder), sodium ascorbate, and N,N-disopropylethylamine in methanol:water to afford amphiphilic triazolyl linear-linear (WG(triazole-KR-NH2))3 and cyclic-linear [WG(triazole-KR-NH2)]3 peptides, respectively. The secondary structures of both peptides were similar to a distorted α-helix as shown by CD spectroscopy. TEM imaging showed that linear-linear (WG(triazole-KR-NH2))3 and cyclic-linear [WG(triazole-KR-NH2)]3 peptides formed nano-sized structures in the size range of 50-100 nm and 50-80 nm, respectively.

Ab Initio Study of Non-Peptidic Antihypertensives

In this study, the authors report ab initio molecular orbital calculations on natural hormone angiotensin II (ANG II) that induces activity at AT1 receptor leading to vasoconstriction and subsequent hypertension. Optimized conformations and charge distributions of various conformers of natural hormone and AT1 antagonists have been studied. The major pharmacophoric features have been deduced. The charge environment of ANG II and drugs guided us in exploring the two possibilities: substrate inhibition and competitive inhibition. The results indicate that more potent drugs avoid ‘wastage’ in substrate inhibition and undergo strong competitive antagonism at the receptor. Specific binding interactions are essential for competitive antagonism. Slight differences in conformation may effect to differences in interactions with the receptor, hence modulating the antagonistic properties of the drug.

An ab initio study of AT2 antagonists.

In this study we report ab initio molecular orbital calculations on the natural hormone angiotensin II, which induces activity at AT1/AT2 receptor subtypes leading to vasoconstriction and subsequent hypertension, and AT2 antagonists. Pharmacophoric features of AT2 antagonists have been studied. A model of AT2 receptor has been made, and angiotensin II as well as antagonists has been systematically docked and their interactions with the receptor analyzed. Calculated ligand–receptor interaction energies have been correlated with experimentally observed biological potency data. Our studies indicate that antagonists retain sufficient interactions to block the receptor but may not be adequate to induce activity at the receptor. A poor antagonist is, therefore, proposed as a close mimic of angiotensin II in terms of interacting with the receptor. These studies further explore the mechanistic aspects of this important class of drugs.

Non-covalent carriage of anticancer agents by humanized antibody trastuzumab

AbstractThis article explores the internalization and non-covalent carriage of small molecule anticancer agents like vinca alkaloids by humanized monoclonal antibody trastuzumab. Such carriage is marked by significant reduction in side effects and increased therapeutic value of these anticancer agents. This study is coherent with few clinical observations of enhanced efficiency of these anticancer agents when co-administered with therapeutic antibodies. This study will also serve as the foundation for screening a database of anticancer agents for possible compounds that may be co-delivered alongwith the antibody. Based on this study vincristine conformation inside antibody and its charge environment may be used as descriptors for screening purposes. Graphical AbstractThis article describes the use of immunotherapeutic agents for enhancing the bioavailability and efficacy of small molecule anticancer agents. The internalization and non-covalent carriage of vinca alkaloids by humanized antibody trastuzumab has been investigated utilizing flexible ligand molecular docking and molecular dynamics simulation studies coupled with MMGBSA binding energy calculations. The study concludes efficient non-covalent carriage without probability of premature expulsion. It is recommended that vincristine conformation and charge distribution may be used for screening library of compounds for possible mAb cargo