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.

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.

No abstract

No abstract

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.

No abstract

The cdc25 family of phosphatases plays a vital role in cell cycle regulation. The role of CdC25B (one of the isoforms of CdC25) in tumor cell growth is well recognized. All the active site of the CdC25 proteins has the consensus Cys-X5-Arg motif. Based on the three-dimensional structural studies, the role of the cysteine and arginine residues in CdC25B proteins are accurately established. Alteration of either the cysteine and arginine residues of the Cys-X5-Arg motif led to the loss of both reductase and phosphatase activities. R is a highly conserved arginine that hydrogen bonds to the phosphorylated amino acid of the substrate. Structural evidence suggests that the toxic metals like arsenic bind strongly to cysteine the carbonyl group of residue Cys477 in Ccd25B points toward the location where phosphate should bind. Recently Lund et al. [1] have identified two potential inhibitors for CdC25B (PDB ID: 4WH7, and 4WH9). Interestingly these small molecules [2fluoro-4-hydroxybenzonitrile and 2-[(2-cyano-3-fluoro-5-hydroxyphenyl) sulfanyl] ethanesulfonic acid] bound to a different pocket primarily comprised of Phe386, Leu398, Cys484, Arg488, and Met505 on CdC25B located approximately 15 Angstrom away from the Cys-X5-Arg active site. This alternative active site is relatively more polar and connects well with water hydrogen bonding network. Currently, we have proposed a set of 34 novel compounds, which may be the potential inhibitors for CdC25B. The molecular docking technique has been employed to identify the affinity of the molecules, and all the compounds were docked in all major active sites. The result suggest that 3-[(pyridin-4-yl)methyl]-3azatricyclo[7.3.1.05,13] trideca-1(12),5,7,9(13),10-pentaene-2,4-dione&8-bromo-3-[(pyridin-4-yl)methyl]-3-azatricyclo [7.3.1.05,13] trideca-1(12),5,7,9(13),10-pentaene-2,4-dione) (-7.1 kcal/mol,-6.4 kcal/mol) has better affinity than the molecules identified by Lund et al. (-5.1kcal/mol) [1]. And these molecules also have better hydrogen bonding and hydrophobic interactions with several amino acids in the secondary active site. The proposed molecules docked at Cys-X5-Arg active site, revealed some interesting protein interactions. In summary, we identified some novel high-affinity inhibitor molecules to block the activity of CdC25b phosphates, which may provide an opportunity to target this important class of proteins.

Background: Cereblon, an extensively studied multifunctional protein, is a Cullin 4-RING E3 ubiquitin ligase complex component and a well-known target of thalidomide and its derivatives. Cereblon is involved in the apoptosis of multiple myeloma cells. When ligands such as 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 cereblon inhibitors were investigated by molecular docking. ADME/T and drug-likeness properties of the molecules were studied. A molecular dynamics study was carried out for 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. DHFO creates an interaction hotspot on the cereblon surface, thereby serving as a novel alternative for thalidomide and its derivatives. Ease of chemical synthesis, low toxicity, versatile therapeutic options, and pleiotropism of DHPO analogues 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.