Elucidating arsenic-bound proteins in the protein data bank: data mining and amino acid cross-validation through Raman spectroscopy.

The International Agency for Research on Cancer has unequivocally classified inorganic arsenic as a Group 1 carcinogen, definitively establishing its potential to induce cancer in humans. Paradoxically, despite its well-documented toxicity, arsenic finds utility as a chemotherapeutic agent. Notable examples include melarsoprol and arsenic trioxide, both employed in the treatment of acute promyelocytic leukemia. In both therapeutic and hazardous contexts, arsenic can accumulate within cellular environments, where it engages in intricate interactions with protein molecules. Gaining a comprehensive understanding of how arsenic compounds interact with proteins holds immense promise for the development of innovative inhibitors and pharmaceutical agents. These advancements could prove invaluable in addressing a spectrum of arsenic-related diseases. In pursuit of this knowledge, we undertook a systematic exploration of the Protein Data Bank, with a focus on 902 proteins intricately associated with 26 arsenic compounds. Our comprehensive investigation reveals insights into the interactions between these arsenical compounds and amino acids located within a 4.0 Å molecular distance from arsenic-binding sites. Our findings identify that cysteine, glutamic acid, aspartic acid, serine, and arginine frequently engage with arsenic. In complement to our computational analyses, we conducted rigorous Raman spectroscopy studies on the top five amino acids displaying robust interactions with arsenic. The results derived from experimental Raman spectroscopy were meticulously compared with our computational assessments, thereby enhancing the reliability and depth of our investigations. The current study presents a multidimensional exploration into the elaborate interplay between arsenic compounds and proteins. By elucidating the specific amino acids that preferentially interact with arsenic, this study not only contributes to the fundamental understanding of these molecular associations but also lays the foundation for future endeavors in drug design and therapeutic interventions targeting arsenic-related illnesses. Our work at the convergence of toxicology, medicine, and molecular biology carries profound implications for advancing our knowledge of arsenic's dual nature as both a poison and a potential cure.

Computational investigations of indanedione and indanone derivatives in drug discovery: Indanone derivatives inhibits cereblon, an E3 ubiquitin ligase component.

BACKGROUND: Cereblon, an extensively studied multifunctional protein, is a Cullin 4-RING E3 ubiquitin ligase complex component. Cereblon is a well-known target of thalidomide and its derivatives. Cereblon is involved in multiple myeloma cell apoptosis. When ligands such as thalidomide and lenalidomide bind to cereblon, it recognizes various neosubstrates based on the ligand shape and properties. We have identified novel CRBN inhibitors, namely DHFO and its analogs, with structural features that are slightly different from thalidomide but stronger cereblon-binding affinity. We selected indanedione and indanone derivatives from the literature to understand and compare their cereblon-mediated substrate recognition potential. METHODS: Computational investigations of possible CRBN inhibitors were investigated by molecular docking with Autodock Vina and DockThor programs. The properties of the compounds' ADME/T and drug-likeness were investigated. A molecular dynamics study was carried out for four selected molecules, and the molecular interactions were analyzed using PCA-based FEL methods. The binding affinity was calculated using the MM/PBSA method. RESULTS: We conducted computational investigations on 68 indanedione and indanone derivatives binding with cereblon. Ten molecules showed better CRBN binding affinity than thalidomide. We studied the drug-likeness properties of the selected ten molecules, and four of the most promising molecules (DHFO, THOH, DIMS, and DTIN) were chosen for molecular dynamics studies. The MM/PBSA calculations showed that the DHFO, already shown to be a 5-LOX/COX2 inhibitor, has the highest binding affinity of - 163.16 kJ/mol with cereblon. CONCLUSION: The selected CRBN inhibitor DHFO has demonstrated the highest binding affinity with cereblon protein compared to other molecules. Thalidomide and its derivatives have a new substitute in the form of DHFO, which produces an interaction hotspot on the surface of the cereblon. Ease of chemical synthesis, low toxicity, versatile therapeutic options, and pleiotropism of DHFO analogs provide an opportunity for exploring clinical alternatives with versatile therapeutic potential for a new category of indanedione molecules as novel modulators of E3 ubiquitin ligases.

Thermal Energy Electrons and OH-Radicals Induce Strand Breaks in DNA in an Aqueous Environment: Some Salts Offer Protection Against Strand Breaks.

Electrons and •OH-radicals have been generated by using low-energy laser pulses of 6 ns duration (1064 nm wavelength) to create plasma in a suspension of plasmid DNA (pUC19) in water. Upon thermalization, these particles induce single and double strand breakages in DNA along with possible base oxidation/base degradation. The time-evolution of the ensuing structural modifications has been measured; damage to DNA is seen to occur within 30 s of laser irradiation. The time-evolution is also measured upon addition of physiologically relevant concentrations of salts containing monovalent, divalent, or trivalent alkali ions. It is shown that some alkali ions can significantly inhibit strand breakages while some do not. The inhibition is due to electrostatic shielding of DNA, but significantly, the extent of such shielding is seen to depend on how each alkali ion binds to DNA. Results of experiments on strand breakages induced by thermalized particles produced upon plasma-induced photolysis of water, and their inhibition, suggest implications beyond studies of DNA; they open new vistas for utilizing simple nanosecond lasers to explore the effect of ultralow energy radiation on living matter under physiologically relevant conditions.

Strong Strand Breaks in DNA Induced by Thermal Energy Particles and Their Electrostatic Inhibition by Na+ Nanostructures.

Low-power laser pulses of 6 ns duration (1064 nm wavelength) have been used to create plasma in an aqueous solution of plasmid DNA (pUC19). Thermal energy electrons and •OH radicals in the plasma induce strand breakages in DNA, including double strand breaks and possible base oxidation/base degradation. The time evolution of these modifications shows that it takes barely 30 s for damage to DNA to occur. Addition of physiologically relevant concentrations of a salt (NaCl) significantly inhibits such damage. We rationalize such inhibition using simple electrostatic considerations. The observation that DNA damage is induced by plasma-induced photolysis of water suggests implications beyond studies of DNA and opens new vistas for using simple nanosecond lasers to probe how ultralow energy radiation may affect living matter under physiological conditions.

Homology Modeling and Docking Studies of Bcl-2 and Bcl-xL with Small Molecule Inhibitors: Identification and Functional Studies.

Apoptosis is a vital physiological process, which is observed in various biological events. The anti-apoptotic and pro-apoptotic members of Bcl-2 family are the most characterized proteins which are involved in the regulation of apoptotic cell death. The anti-apoptotic proteins such as Bcl-2 and Bcl-xL prevent apoptosis, whereas pro-apoptotic members like Bax and Bak, elicit the release of caspases from death antagonists inducing apoptosis. Thus, the Bcl-2 family of proteins play a vital role in controlling programmed cell death. Over expression of anti-apoptotic Bcl-2 proteins are often directly associated with various kinds of cancer. Developing suitable inhibitors for controlling the elevated levels of these proteins got much attention in last decade. Structural biology techniques such as Nuclear Magnetic Resonance (NMR) spectroscopy, X-ray crystallography, homology modeling and molecular docking play a significant role in identifying the key inhibitors of these proteins. The authors have developed and tested successfully, several series of indole pharmacore containing inhibitors for Bcl-2 and Bcl-xL proteins based on the homology modeling, docking and suitable biochemical and apoptosis assays. This review provides a summary of potential inhibitor molecules developed for Bcl-2 and Bcl-xL proteins, as well as the the key residues of these proteins interacting with potential drug molecules. The present appraisal also focuses on the role of computational algorithms in developing potential drug molecules,with more emphasis on the role of homology modeling and docking studies in developing inhibitors for Bcl- 2, and Bcl-xL proteins in cancer therapy.