Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators.
Structure-activity relationship study of vitamin D analogs with oxolane group in . thiazolidinones as potent tyrosinase inhibitors: SAR and molecular modeling. Structural modifications of N-arylamide oxadiazoles: Identification of Structure– activity relationship studies on vitamin D lactam derivatives as vitamin D receptor antagonist .. Imidazole piperazines: SAR and development of a potent class of. STRUCTURE-ACTIVITY RELATIONSHIP OF CAROTENOID DERIVATIVES IN . of vitamin D, on colon cancer is usually attributed to its anti-proliferative and.
Due to the high cost of managing SCD, research has been on-going on the exploration of medicinal plants to address the multiple health challenges presented by the disease [ 7 ].
To prevent polymerization of haemoglobin and vascular occlusions, extracts of medicinal plants have been used in folk medicine in the management of SCD. The observed therapeutic effect of these herbs may be as a result of combined antisickling, anti-polymerization, anti-dehydration, anti-inflammatory and antioxidant effects from the components of the plants, which is typical of most herbal remedies. P-Hydroxy-benzoic acid has also been reported to have antibacterial against Gram positive and negative bacteriaantifungal, anti-algal, antimutagenic and estrogenic activity [ 10 ].
Vanillin is known to inhibit gelation of haemoglobin and markedly increases oxygen affinity of both normal HbA and abnormal HbS haemoglobin [ 1112 ]. The anti-sickling properties of p-fluorobenzoic acid have been reported by Elekwa and his colleagues [ 13 ]. Ferulic acid is a hydroxycinnamic acid, a type of organic compound.
Aromatic aldehydes form Schiff bases with haemoglobin and were designed as potential anti-sickling agents as they reduce the ability of HbS to polymerise on deoxygenation [ 1112 ]. Ferulic acid, like many natural phenols, is an antioxidant in vitro in the sense that it is reactive toward free radicals such as reactive oxygen species ROS. Its anti-sickling properties were established by [ 14 ]. Diverse biochemical reactions take place during the biosynthesis of SKA namely: Among the aromatic compounds synthesized via shikimate pathway are 4-hydroxybenzoic acid, salicylic acid, p-amino benzoic acid PABA which forms part of the structure of folic acid vitamin B9 a molecule used in the management of SCD.
Folic acid Figure 3 is found in yeast, liver, and green vegetables. It is a thermodegradable compound. Salicin Salix species; Salicaceae is responsible for the analgesic and antipyretic effects of willow barks, widely used for centuries, and the template for synthesis of acetylsalicylic acid aspirin as a more effective analogue. Chemically, Aspirin has a similar core structure as Salicin or salicylic acid which is synthesized in microorganisms from isochorismic acid and in plants by two other mechanisms: NSAIDs are a chemically heterogeneous group of organic acids that share certain therapeutic actions and adverse effects.
The similarities observed in structure can explain why these compounds share the same bioactive properties. The acetyl-3,5- dibromosalicylic acid dibromo aspirina derivative of aspirin, has been reported to exhibit the erythrocyte sickling [ 15 ]. Acetylation of hemoglobin by aspirin and other acetylating agents has been used to generate haemoglobin analogs with altered structural and functional properties, and may prove useful in the treatment of sickle cell disease [ 16 ].
Aspirin inhibits the COX enzymes but in a manner molecularly distinct from the competitive, reversible, active site inhibitors and is often distinguished from the NSAIDs. In this regard, a number of structure activity relationship studies employing both in silico and experimental techniques have been reported. In this review, we focus on SAR studies around antisickling agents possessing a benzoic acid core scaffold and other related derivatives.
Mathematical modeling techniques have been employed in predicting the antisickling activities of benzoic acid derivatives. Employing such mathematical modeling approaches, Fasanmade et al. Derivatives predicted to be active by the mathematical model were tested experimentally and these included p-toluic acid, p-dimethylaminobenzoic acid, p-fluorobenzoic acid, p-chlorobenzoic acid, m-chlorobenzoic acid, p-bromobenzoic acid, p-nitrobenzoic acid, and p-iodobenzoic acid Figures After analyzing a series of equations correlating biological activities with the structures of the tested derivatives, Fasanmade et al.
Other studies have also revealed promising antisickling activity of benzoic acid derivatives.
InAbraham et al. The designing of the disubstituted benzoic acid derivatives involved the use of molecular modeling techniques. Such a design ensured the strategic positioning of functional groups to facilitate their interaction with several polar amino acid residues near the Valine-6 beta mutation site in sickled haemoglobin HbS.
A hydrophobic group the phenyl core was also rationally incorporated to occupy a nonpolar area on the surface of the protein created by several hydrophobic amino acids.
Synthesis and antigelling evaluation of these rationally designed target compounds gave rise to derivatives with promising antisickling activities. The students in the Arnold Group will learn different techniques of modern drug discovery. Assay development, high-throughput screening, data analysis, and data mining Hit compound validation using biochemical, biophysical and cell-based assays and determination of their mode of action Organic chemistry including the synthesis of bioactive scaffolds, hit compound structure-activity relationship studies SARand parallel synthesis of small focused libraries in solution and on solid support Virtual screening, pharmacophore modeling and docking Pharmacological profiling of biomedical probes including ADME The interdisciplinary research conducted in the Arnold Group combines the traditional fields of organic chemistry, biochemistry, analytical chemistry, and pharmacology to develop bioactive probes to investigate the underlying biomolecular pathways of human diseases.
Reseach Area Protein-protein interactions are essential for signal transduction in all living organisms. Many of these interactions have been revealed by means of biochemical assays but only a few interactions have been elucidated on a molecular level. The Arnold Group investigates small molecules with the ability to mimic the binding mode of short alpha-helical protein sequences.
Examples are interactions between nuclear receptors NRs and transcriptional coregulators, which are essential for NR mediated gene regulation. Due to the wide range of physiological processes regulated by NRs, small molecules targeting NRs often cause various side effects. Thus, there is still a great need for development of new approaches to regulating NR function. The vitamin D receptor VDR is one of 48 nuclear receptors identified in the human genome.
Its structural organization consists of a ligand-independent transactivation domain AF-1 at the amino terminus, a central DNA binding domain DBDand a ligand binding domain LBD including the allosteric ligand dependent activation function AF The binding of 1,Dihydroxyvitamin D3 to VDR activates specific gene regulation, which is governed by the recruitment of coregulators.
Alexander (Leggy) Arnold | Chemistry & Biochemistry
The development of small molecules with the ability to inhibit the interaction between specific coregulators and VDR represents a new approach towards modulating NR signaling.
Chemistry plays an essential role developing these molecules into biochemical probes allowing investigations of biological effects of specific VDR-coregulator inhibition in cells and organisms.Vitamin D3 Deficiency ? - Dr Shalini
Interestingly, these CBIs act complementary to the ligand based strategy to modulate VDR mediated signal transduction. The investigation of synergistic behavior between ligand and CBI might represent an important strategy to overcome hormone independent or hormone resistant NR signaling which represents a major problem for NR ligand based treatments such as cancer.
The GABA A receptor is a pentameric membrane receptor that is expressed in neurons but also in many other cell types. The receptor respond to GABA with increased chloride influx causing hyperpolarization and therefore an increased cell membrane potential.
This in turn regulates muscle function and immune response, two important hallmarks to combat asthma.
Alexander (Leggy) Arnold
Our group works together with the Cook Group who is responsible for the synthesis of new GABA A receptor ligands to overcome the pharmacological shortcomings of earlier ligands to develop a new systemic treatments for asthma. Important for our strategy is the inability of ligands to cross the blood-brain-barrier. Selected Publications Gloria S.