Chemicals and Drugs Commons^™

Adenosine Dimethyltransferase Ksga: Biochemical Characterization Of The Protein And Its Interaction With The 30s Subunit, Pooja Desai

Theses and Dissertations

Ribosomes form the core of the protein biosynthesis machinery and are essential to life. Ribosome biogenesis is a complex cellular process involving transcription of rRNA, pre-rRNA processing, rRNA modification and simultaneous assembly of ribosomal proteins. RNA nucleotide modification is observed in all domains of life. While there is enormous conservation of ribosome structure, very few post-transcriptional rRNA modifications have been conserved throughout evolution. A notable example of such rare conservation is the dimethylation of two adjacent adenosines in the 3’-terminal helix, a highly conserved region of the small subunit rRNA. Enzymes that carry out these dimethylations are equally conserved and …

Mutagenesis And Spectroscopic Studies Of Mycobacterium Tuberculosis Sterol 14alpha Demethylase., Anuja R. Modi

Theses and Dissertations

P450s are heme containing enzymes which affect oxidation of substrates via catalytic intermediates having transient lifetimes. These oxidative catalytic intermediates are formed by a sequential interplay of electrons and protons at the active site of the enzyme bearing molecular dioxygen. The proton transfer to the active site from bulk solvent is coordinated by an “acid-alcohol” pair of active site residues which are conserved in all P450s. Sterol 14α-demethylases (CYP51) are P450 enzymes which catalyze oxidative deformylation of lanosterol in the cholesterol/ergosterol biosynthetic pathway. Both cholesterol and ergosterol are important regulators of membrane fluidity. CYP51 differs from other P450s in that …

Novel Allosteric Inhibitors Of Thrombin, Bijoy Desai

Theses and Dissertations

Thrombin is a critical enzyme involved in blood coagulation and haemostasis. For this reason the study of its interactions with substrates, inhibitors and modulator is essential. It is also a unique enzyme in the serine protease family because unlike enzymes like trypsin and chymotrypsin its activity is modulated by various endogenous and exogenous ligands. This is due to the presence of “exosites” on the thrombin surface. Exosite II, unlike exosite-I, has not been characterized for its allosteric effect. In order to understand the structural basis of interaction and inhibition of inhibitor 4AS, which possibly interacts with exosite-II, native bovine thrombin …

Synthesis And Biochemical Studies On Sulfated Monomers Of Low Molecular Weight Lignins, Jenson Verghese

Theses and Dissertations

Anticoagulants are used as the first line therapy for management and prevention of thrombotic disorders. Thrombin and factor Xa have been the prime targets for regulation of the coagulation cascade. In this work, a small library of 17 benzofuran derivatives were synthesized and screened against thrombin and factor Xa. The derivatives that displayed inhibitory potential were docked on the exosite-II of factor Xa using a docking protocol that was developed in our research group. These compounds were based on the β-5 structural unit found in the oligomer -'CDSO3‘, which was prepared in our lab and was found to inhibit both …

Development Of Hint Based Computational Tools For Drug Design: Applications In The Design And Development Of Novel Anti-Cancer Agents, Ashutosh Tripathi

Theses and Dissertations

The overall aim of the research is to develop a computational platform based on HINT paradigm for manipulating, predicting and analyzing biomacromolecular-ligand structure. A second synergistic goal is to apply the above methodology to design novel and potent anti-cancer agents. The crucial role of the microtubule in cell division has identified tubulin as an interesting target for the development of therapeutics for cancer. Pyrrole-containing molecules derived from nature have proven to be particularly useful as lead compounds for drug development. We have designed and developed a series of substituted pyrroles that inhibit growth and promote death of breast tumor cells …

“Design And Synthesis Of Molecular Probes For The Study Of 5-Ht2a And H1 Receptors”, Jitesh Shah

Theses and Dissertations

The serotonin (5-HT) receptors, with seven subtypes and at least fifteen distinct members, mediate a wide range of physiological functions both in the central nervous system and in the periphery. All members of the 5-HT family except the 5-HT3 subtype belong to the family of aminergic G protein-coupled receptors (GPCRs). Over the years, various molecules have been reported which act selectively at 5-HT2 receptors. However, there are no ligands that exhibit complete selectivity for one subpopulation of 5-HT2 receptors. Insight into how drugs bind to 5-HT2 receptors could contribute significantly to the development of subtype-selective agents with enhanced therapeutic effects. …

Development Of Ppar-Γ Receptor Agonists As Therapeutic Agents For Diabetes, Ashwini Goswami

Theses and Dissertations

The peroxisome proliferator-activated receptors (PPARs) are the transcriptional regulators of glucose, lipids and cholesterol metabolisms. It has been established that PPAR-γ is the receptor for thiazolidinediones (TZDs) class of type II anti-diabetic drugs. These compounds act as agonists of PPAR-γ. They may delay the development of type II diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. PPAR-γ receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin (responsible for glucose regulation and fatty acid metabolism) and …

Novel Analogs Of M-Chlorophenylguanidine As 5-Ht3 Receptor Ligands, Katie Alix

Theses and Dissertations

Serotonin receptors play a variety of functional roles in the body. Some indications and treatment claims for one of the classes of serotonin receptors, the 5-HT3 receptor family, include: anxiety, depression, chemotherapy- and radiation-induced emesis, constipation, irritable bowel syndrome, pain, drug addiction, and satiety control. A 5-HT3 receptor partial agonist, MD-354, served as a lead compound in the development of new 5-HT3 receptor ligands. Using halogenated analogs the study investigated their effect on binding to the 5-HT3 receptor. Conformationally-constrained analogs (quinazolines) were shown to be a novel class of 5-HT3 receptor antagonists. The log P values were determined for several …

Salvinorin A: Fragment Synthesis And Modeling Studies, Donna Mcgovern

Theses and Dissertations

Salvinorin A is a non-nitrogenous, selective kappa opioid receptor agonist with potent hallucinogenic properties. Because Salvinorin A has no basic nitrogen, it does not readily adhere to the “message-address” concept of selectivity for the opioid receptors. Therefore, a better understanding of how salvinorin A and its analogs interact with the kappa opioid receptor may shed some light on how salvinorin A obtains its potency and selectivity. The structure-affinity relationships (SAFIR) of salvinorin A and its analogs along with a discussion of the selectivity of the opioid receptors, is presented. A fragment of salvinorin A, methyl-3-acetoxy-4-oxocyclohexanecarboxylate, was synthesized to determine if …

Molecular Modeling Studies Of Heparin And Heparin Mimetics Binding To Coagulation Proteins, Chandravel Krishnasamy

Theses and Dissertations

Heparin, a glycosaminoglycan (GAG), is a complex biopolymer of varying chain length and consisting of uronic acid and glucosamine residues, which are sulfated at various positions. The interaction of heparin with antithrombin is the basis for anticoagulation therapy. Heparin accelerates the antithrombin mediated inhibition of factor Xa and thrombin by a conformational activation mechansism and bridging mechanism, respectively. The sequence specific pentasaccharide DEFGH in full length heparin is the most important fragment for high affinity and activation of antithrombin, without which the heparin is incapable of binding to antithrombin. Although heparin is a commonly used anticoagulant, it suffers from serious …

Selective Non-Peptide Mu-Opioid Receptor Antagonist: Design, Synthesis And Biological Studies, Lindsey Aschenbach

Theses and Dissertations

There are currently many opioid agonists available for clinical use as analgesics. However, many of these opioid agonists have notorious side effects including respiratory depression and may lead to addiction and dependence. Problems associated with these opioid agonists are determined to come from their interactions with the mu-opioid receptor. Opioid antagonists, such as naltrexone, have shown to aid in the treatment of opioid addiction. Although naltrexone has high affinity to the mu-opioid receptor, it lacks selectivity. Novel selective mu-opioid receptor antagonists were designed based on the identification of important pharmacophore elements in several known mu-opioid receptor agonists and antagonists. These …

Designing Non-Saccharide Heparin/Heparan Sulfate Mimics, Arjun Raghuraman

Theses and Dissertations

Glycosaminoglycans (GAGs) are complex biopolymers that play important roles in inflammation, coagulation, angiogenesis, cell adhesion and viral invasion by interacting with several different proteins.1,2 Structurally, GAGs are built up of several different sulfated disaccharide units.3 Specific GAG sequences that uniquely recognize their cognate proteins exist. Such specificity typically arises from the binding of unique sulfation patterns on the linear GAG chain to highly electropositive protein domains. Thus, these highly charged, sulfated biopolymers potentially represent a new class of therapeutics. Yet, the major stumbling block to the development to these agents is their extremely complicated and tedious chemical synthesis. We hypothesized …

Characterization Of Yeast 18s Rrna Dimethyl Transferase, Dim1p, Nagesh Pulicherla

Theses and Dissertations

Eukaryotic ribosome biogenesis, a dynamic and coordinated multistep process which requires more than 150 trans-acting factors, has been intensely studied in the yeast Saccharomyces cerevisiae. This evolutionarily conserved process involves numerous cleavages of pre-rRNA, modification of nucleotides, and concomitant assembly of the ribosomal proteins onto the rRNA. Considerable information is available about the importance of conserved pre-rRNA cleavage events in ribosome biogenesis; however, very little is known about the exact role of modified nucleotides, which cluster within the functionally important regions of the ribosome. One conserved group of modifications is the dimethylation of two adjacent adenosines at the 3´ end …

5-Ht3 Receptor Ligands And Their Effect On Psychomotor Stimulants, Jessica Nicole Worsham

Theses and Dissertations

Drug abuse and addiction are considered to be a result, at least in part, of the rewarding effects produced by increasing dopamine levels. 5-HT3 serotonin receptors have been shown to indirectly affect dopamine levels. Therefore, the effect of the 5-HT3 receptor partial agonist, MD-354, on the actions of psychomotor stimulants was analyzed in mouse locomotor activity assays to determine whether MD-354 is working through a 5-HT3 receptor agonist or antagonist mode of action. Studies with (+)amphetamine and (+)methamphetamine in combination with MD-354 indicated MD-354 is either devoid of action or is behaving similar to the 5-HT3 receptor antagonist, ondansetron. This …

Novel Sulfated 4-Hydroxycinnamic Acid Oligomers As Potent Anticoagulants, Brian Lawrence Henry

Theses and Dissertations

The occurrence of thrombosis in several pathophysiological conditions creates a huge need for anticoagulation therapy. Thrombin and factor Xa have been prime targets for regulation of clotting through the direct and indirect mechanism of inhibition. This work investigates chemo-enzymatically prepared oligomers of 4-hydroxycinnamic acids (DHPs) as potential anticoagulants. Oligomers were prepared through peroxidase-catalyzed oxidative coupling of 4-hydroxycinnamic acids. The products resulting from this reaction are called CDs, FDs and SDs. Structurally, these sulfated DHPs are unique and do not resemble any of the anticoagulants known in the literature.DHP oligomers were found to increase clotting times at concentrations comparable to heparin. …

Interactions Of Mtfabh With Its Substrates And Inhibitors Reveal Novel Mechanistic Insights, Sarbjot Singh Sachdeva

Theses and Dissertations

Tuberculosis emerged from its grave to be one of the deadliest diseases of the present time after recently developing a synergy with AIDS. A fatty acid condensing enzyme-mtFabH has been proposed to connect the key processes involved in biosynthesis of mycolic acids, an important component of mycobacterial cell wall. It condenses long acyl Coenzymes A (CoA; up to C20CoA) with malonyl Acyl Carrier Protein (ACP) to form the elongated β-ketoacyl-ACP which further undergoes rounds of elongation to form mero-mycolate branch of mature mycolic acids. Owing to its proposed central position in mycolic acid synthesis, mtFabH has attracted considerable attention as …

On The Binding Of N1-Substituted Tryptamines At H5-Ht6 Receptors, Abner Nyamwaro Nyandege

Theses and Dissertations

Serotonin was first discovered in the late 1940s as a vasotonic factor and is now considered a principal neurotransmitter in the nervous system. 5-HT6 receptors are one of the most recently identified members of the serotonin receptor family which consists of seven classes (5-HT1-5-HT7). 5-HT6 receptors are G-protein coupled, positively coupled to an adenylate cyclase second messenger system and are primarily found in the central nervous system (CNS). The exact functional role of 5-HT6 receptors has not been determined, but is implicated to have possible involvement in certain neuropsychiatric disorders and cognition. To investigate the functional role of these receptors, …

Identification Of Novel Allosteric Regulators Of Human Erythrocyte Pyruvate Kinase, Shilpa S. Kharalkar

Theses and Dissertations

Erythrocyte pyruvate kinase (R-PK) is a key glycolytic enzyme catalyzing the transphosphorylation of phosphoenolpyruvate (PEP) and ADP to pyruvate and ATP respectively3,4. The substrate PEP and product pyruvate of this reaction are involved in a number of energetic and biosynthetic pathways; hence a tight regulation of R-PK activity is crucial not only for glycolysis, but also for the entire cellular metabolism. Deficiency of R-PK is one of the most common enzymatic defects of RBC, and may be caused by mutations of the PK-LR (pyruvate kinase liver red blood cell) gene31, 32. Clinically, R-PK deficiency manifests itself as a chronic life-long …

Discovery Of Lignin Sulfate As A Potent Inhibitor Of Hsv Entry Into Cells, Jay N. Thakkar

Theses and Dissertations

The herpes virus family consists of more than hundred members that infect organisms, of which eight, differing markedly in the biology are known to infect humans. HSV- I is the most common one, causing oral lesions and sporadic encephalitis. These infections are highly prevalent affecting at least one in three individuals in the United States.The entry of the herpes virus into the cell is a two-step process. The initial step involves the cell surface heparan sulfate and glycoproteins in the viral envelope which enables the virus to penetrate into the cell. The second step is the fusion step. Depending on …

Dual Mechanism Analgesia-Enhancing Agents, Shawquia Elithia Young

Theses and Dissertations

Currently, there is an increasing need for novel analgesics that are potent but lack undesired side effects. Recent studies have shown that both 5-HT3 receptors and α2B- adrenoceptors play a role in antinociception. MD-354, N-(3-chlorophenyl)guanidine, has a high-affinity both for 5-HT3 and α2B- adrenoceptors and could be viewed as the first example of a rather selective 5-HT3/α2B- adrenoceptor ligand. MD-354, inactive by itself, potentiates the antinociceptive effects of an inactive dose of clonidine in the mouse tail- flick assay. An attempt to determine the underlying mechanism of this potentiating effect was the purpose of the present investigation. The studies focused …

Stability Study Of Phoslactomycin B And Analysis Of Degradation Products, Choudhuri Suparna Das

Theses and Dissertations

Phoslactomycin B (PLM-B), a potent and selective inhibitor of serine threonine phosphatase is of interest for its antitumor, antifungal and antiviral activity. The objective of this study was to evaluate the stability of phoslactomycin B at various pH and temperature conditions. Phoslactomycin B was produced from the mutant strain NP1 of Streptomyces sp.HK-803 and was purified by semi-preparative HPLC . A study of PLM-B degradation was carried out in the pH range of 2-10 at 30ºC and 50°C using HPLC. The PLM-B decomposition was observed to exhibit a U-shaped pH profile and demonstrated both acid and base-catalyzed decomposition. The decomposition …

New Antimuscarinic Agents For Improved Treatment Of Poisoning By Cholinesterase Inhibitors, Robert Lee Hudkins

Theses and Dissertations

Poisoning by organophosphate cholinesterase inhibitors results in a rapid rise in acetylcholine (ACh) in the synapse and many pronounced pharmacological effects in numerous tissues in the body. The treatment for organophosphorus poisoning involves administration of a cholinesterase—reactivating oxime to restore the activity of the cholinesterase and an antimuscarinic agent to block the response to the excess ACh. Presently atropine is the standard antimuscarinic agent used clinically as an antidote. This research was directed toward finding an antimuscarinic agent better than atropine as an antidote.

Since caramiphen and aprophen have been reported to be effective antidotes we synthesized numerous structural variations …