Neuroendocrine Tumor of the Ampulla of Vater: A Case Report.

Neuroendocrine tumors (NETs) of the ampulla of Vater are extremely rare. Here, we discuss the clinical presentation, diagnostic challenges, and treatment options of a recently experienced case of NET of the ampulla of Vater in light of the literature. A 56-year-old woman presented with recurrent upper abdominal pain. Ultrasonography (USG) of the whole abdomen showed multiple gallstones along with a dilated common bile duct (CBD). For evaluating the dilated CBD, a magnetic resonance cholangiopancreatography was performed, which revealed the double-duct sign. Subsequently, an upper gastrointestinal endoscopy showed a bulged-out ampulla of the Vater. Biopsy and histopathological examination of the growth yielded the diagnosis of adenocarcinoma. A Whipple procedure was performed. Macroscopically, a 2 cm growth was noted involving the ampulla of Vater, and microscopic findings were consistent with a well-differentiated NET, grade 1 (low grade). The diagnosis was further confirmed by immunohistochemical staining (pan-cytokeratin positive, synaptophysin positive, and focally chromogranin positive). Her postoperative course was uneventful except for delayed gastric emptying. A detailed evaluation and a high index of suspicion are required for the diagnosis of this rare tumor. Treatment is relatively easier after a proper diagnosis.

QSAR Studies to Predict Activity of HSP90 Inhibitors.

Heat shock protein 90 (HSP90) is a multichaperone complex that mediates the maturation and stability of a variety of oncogenic signaling proteins. HSP90 has emerged as a promising target for the development of anticancer agents. Heterocyclic chemical moieties with HSP90 inhibitory activity were studied continuously during the last decades, and resulting data were applied by medicinal chemists to design and develop new drugs. Their structure-activity relationship (SAR) studies and QSAR models have been derived to assist the current drug development process. The QSAR models are obtained via multiple linear regression (MLR) and non-linear approaches. Interpretation of the reported model highlights the core template required to design novel, potent HSP90 inhibitors to be used as anticancer agents.

Molecular Processes Exploited as Drug Targets for Cancer Chemotherapy.

Cancer is an uncontrolled malignant tumor growth taking place in any tissue of the body and attains complex diversity which makes it difficult for oncologists to choose therapeutics. The changes leading to formation of cancerous cells occur due to a series of molecular events. Now scientists are trying to understand the various molecular processes that are involved in the growth of cancers. This article presents a brief account of epigenetics with reference to DNA methylation and histone modification as an important contributor to the formation of cancer cells. Drug targeting the epigenetic regulators has been considered for various types of cancer. The enzymes in DNA methylation and histone modification, FDA approved clinical drugs along with the challenges associated with the development of anti-cancer target based therapeutics are summarized.

In-silico Studies and Biological Activity of Potential BACE-1 Inhibitors.

BACKGROUND: Alzheimer's disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). OBJECTIVE: The controlled APP processing by inhibition of secretase is the strategy to reduce Aß load to treat Alzheimer's disease. METHODS: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds. RESULTS: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions. CONCLUSION: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1µM.

An Overview of Ovarian Cancer: Molecular Processes Involved and Development of Target-based Chemotherapeutics.

Ovarian cancer is one of the leading gynecologic diseases with a high mortality rate worldwide. Current statistical studies on cancer reveal that over the past two decades, the fifth most common cause of death related to cancer in females of the western world is ovarian cancer. In spite of significant strides made in genomics, proteomics and radiomics, there has been little progress in transitioning these research advances into effective clinical administration of ovarian cancer. Consequently, researchers have diverted their attention to finding various molecular processes involved in the development of this cancer and how these processes can be exploited to develop potential chemotherapeutics to treat this cancer. The present review gives an overview of these studies which may update the researchers on where we stand and where to go further. The unfortunate situation with ovarian cancer that still exists is that most patients with it do not show any symptoms until the disease has moved to an advanced stage. Undoubtedly, several targets-based drugs have been developed to treat it, but drug-resistance and the recurrence of this disease are still a problem. For the development of potential chemotherapeutics for ovarian cancer, however, some theoretical approaches have also been applied. A description of such methods and their success in this direction is also covered in this review.

Progress in Studies on Structural and Remedial Aspects of Newly Born Coronavirus, SARS-CoV-2.

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.

Recent Studies on Design and Development of Drugs Against Alzheimer's Disease (AD) Based on Inhibition of BACE-1 and Other AD-causative Agents.

BACKGROUND: Alzheimer's disease (AD) is one of the neurodegenerative diseases and has been hypothesized to be a protein misfolding disease. In the generation of AD, ß-secretase, γ-secretase, and tau protein play an important role. A literature search reflects ever increasing interest in the design and development of anti-AD drugs targeting ß-secretase, γ-secretase, and tau protein. OBJECTIVE: The objective is to explore the structural aspects and role of ß-secretase, γ-secretase, and tau protein in AD and the efforts made to exploit them for the design of effective anti-AD drugs. METHODS: The manuscript covers the recent studies on design and development of anti-AD drugs exploiting amyloid and cholinergic hypotheses. RESULTS: Based on amyloid and cholinergic hypotheses, effective anti-AD drugs have been searched out in which non-peptidic BACE1 inhibitors have been most prominent. CONCLUSION: Further exploitation of the structural aspects and the inhibition mechanism for ß-secretase, γ-secretase, and tau protein and the use of cholinergic hypothesis may lead still more potent anti-AD drugs.

Quantum Molecular Dynamics, Topological, Group Theoretical and Graph Theoretical Studies of Protein-Protein Interactions.

BACKGROUND: Protein-protein interactions (PPIs) are becoming increasingly important as PPIs form the basis of multiple aggregation-related diseases such as cancer, Creutzfeldt-Jakob, and Alzheimer's diseases. This mini-review presents hybrid quantum molecular dynamics, quantum chemical, topological, group theoretical, graph theoretical, and docking studies of PPIs. We also show how these theoretical studies facilitate the discovery of some PPI inhibitors of therapeutic importance. OBJECTIVE: The objective of this review is to present hybrid quantum molecular dynamics, quantum chemical, topological, group theoretical, graph theoretical, and docking studies of PPIs. We also show how these theoretical studies enable the discovery of some PPI inhibitors of therapeutic importance. METHODS: This article presents a detailed survey of hybrid quantum dynamics that combines classical and quantum MD for PPIs. The article also surveys various developments pertinent to topological, graph theoretical, group theoretical and docking studies of PPIs and highlight how the methods facilitate the discovery of some PPI inhibitors of therapeutic importance. RESULTS: It is shown that it is important to include higher-level quantum chemical computations for accurate computations of free energies and electrostatics of PPIs and Drugs with PPIs, and thus techniques that combine classical MD tools with quantum MD are preferred choices. Topological, graph theoretical and group theoretical techniques are shown to be important in studying large network of PPIs comprised of over 100,000 proteins where quantum chemical and other techniques are not feasible. Hence, multiple techniques are needed for PPIs. CONCLUSION: Drug discovery and our understanding of complex PPIs require multifaceted techniques that involve several disciplines such as quantum chemistry, topology, graph theory, knot theory and group theory, thus demonstrating a compelling need for a multi-disciplinary approach to the problem.

The effect of high intensity ultrasound (HIU) on the kinetics of crystallization of sucrose: Elimination of latent period.

The application of a technique to eliminate the latent period during crystallization of sucrose by high intensity ultrasound (HIU) was investigated in this paper. Employing HIU (20 kHz, 750 W) to crystallization of sucrose, latent period was eliminated and it was found to obey first order kinetics (K ∼10-5s-1) in the temperature range of 30-50 °C. Employing Arrhenius equation, the average energy of activation (Ea) estimated as 5.0 kcal mol-1. Traditional knowledge indicates that crystallization is sufficiently spontaneous; however, the magnitude of "K" and other thermodynamic quantities of the process indicate that crystallization is actually a slow process. Generally, chemical reactions which posses low rate constants, need the high energy of activation. On the contrary, the energy of activation is appreciably less. The energy of activation with a rate constant of the order of 10-5s-1 could be predicted of the order of 20 kcal mol-1 at 27 °C. The low energy of activation for crystallization of sucrose is of interest. A very interesting elucidation can be had from neutron diffraction data and transport property of the sucrose which is discussed in details in this paper.

N-Substituted Aryl Sulphonamides as Potential Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation.

INTRODUCTION: A novel series of multifunctional anti-Alzheimer's agents based on Nsubstituted aryl sulphonamides were designed and synthesized. During in vivo moderate to good anti- Alzheimer's Disease (AD) activity was observed as correlated by the modulation of some selected biochemical markers of AD as well as during behavioral assessment. METHODS: Among the series, some compounds have shown multi-functional potency by inhibition of Acetylcholinesterase (AChE), Scopolamine induced oxidative stress and were found comparable to the standard drug. Successful modulation of biochemical markers of oxidative stress in AD, displays neuroprotective properties and did not exert any significant toxicity. RESULTS AND CONCLUSION: Thus, the present study has evidently shown that these series of compounds have potential to be optimized as anti-AD agents with multi-functional properties. The aryl sulphonamide nucleus might serve as a promising lead candidate for developing novel anti-AD drug.

Designing of Selective γ-Secretase Inhibitory Benzenesulfonamides through Comparative In Vitro and In Silico Analysis.

BACKGROUND: In Alzheimer's disease (AD), the gene mutations have been identified in the amyloid precursor protein (APP), the presenilin-1 (PS1) and -2 (PS2) genes. APP is a transmembrane protein which gets cleaved by α- and ß- secretase enzymes and releases Aß peptides which forms senile plaques in brain tissue. It contributes for local inflammatory response, subsequent oxidative stress, biochemical changes and neuronal death. Targeting the development of Aß aggregates in the senile plaques is an important strategy in the treatment of AD. To facilitate the normal processing of APP, some of the reported approaches are stimulation of α- secretase activity or the modulation/inhibition of the ß- and γ-secretase complex. METHODS: The mechanism of γ-secretase inhibition is targeted based on the QSAR and molecular docking methods. The series based on 3-chloro-2-hydroxymethylbenzenesulfonamide was selected for in silico ligand-based modeling. Significant correlations, between their γ-Secretase inhibitory profile and 2D-descriptors, were obtained through multiple linear regression (MLR) computational procedure. RESULTS: During QSAR nalysis, calculated molar refractivity (CMR) and surface tension (ST) were found to be contributing parameters along with halogen substituent at a particular position. Applicability analysis revealed that the suggested models have acceptable predictability (rpred2 = 0.827). CONCLUSION: The inferences drawn from MLR were utilized to prepare a data set of fourteen substituted benzenesulfonamides (N1-N14). The in silico studies provides strong impetus towards systematic application of such methods during lead identification and optimization.

GENIUS In Silico Screening Technology for HCV Drug Discovery.

The various reported in silico screening protocols such as molecular docking are associated with various drawbacks as well as benefits. In molecular docking, on interaction with ligand, the protein or receptor molecule gets activated by adopting conformational changes. These conformational changes cannot be utilized to predict the 3D structure of a protein-ligand complex from unbound protein conformations rigid docking, which necessitates the demand for understanding protein flexibility. Therefore, efficiency and accuracy of docking should be achieved and various available/developed protocols may be adopted. One such protocol is GENIUS induced-fit docking and it is used effectively for the development of anti-HCV NS3-4A serine protease inhibitors. The present review elaborates the GENIUS docking protocol along with its benefits and drawbacks.

HCV Inhibitors: Role of Compounds from Botanical Sources.

The developing number of hepatitis C virus infected cases worldwide has threatened people's health. The available therapeutic options have low specificity, side effects and high rate of drug resistance and thus potentiate the need for novel effective anti-HCV drugs. Agents obtained from natural sources offer an enormous scope of structural diversity and broad therapeutic range of coverage. This review summarizes the research and development of anti-HCV agents (plant extracts/isolated components) obtained from various natural sources along with the associated mechanism of HCV inhibition. Some of the reported examples include triterpenes, naringenin, Proanthocyanidin, curcumin, Epigallocatechin-3-gallate, quercetin and abrogates having diverse anti-HCV properties. The compiled knowledge regarding anti-HCV agents from natural sources will provide considerable information for developing novel safe and effective anti-HCV drugs.