Veterinary Considerations for the Theoretical Resurrection of Extinct Species

The de-extinction of the dinosaur is a dubious possibility but its consideration brings forth some issues that are at least worthy of scientific discussion. In this review, we discuss two distinct issues that have implications for a de-extinct species such as a dinosaur: the ability, or lack thereof, to safely sedate a rare and potentially fractious animal capable of harming the veterinary staff tasked with its care; and, disease risks associated with a species that has been extinct for millions of years. To identify potential sedatives, comparative pharmacology will be needed to uncover the links between receptor pharmacology and the desired clinical outcomes of activating established alpha-2 adrenergic, opioid, and benzodiazepine receptors. Specific to disease control, it will be necessary to understand the unique susceptibility of the new species to current diseases as well as predicting their reservoir capacity for potential human and veterinary pandemic diseases. While the topics presented herein are not exhaustive, this review highlights some of the foremost research that should be conducted in order to serve the unique veterinary needs of a de-extinct species using the dinosaur as a paradigm. Addressing these issues should be considered if an intact dinosaur genome becomes available, regardless of the feasibility of dinosaur resurrection

Optimized Hydrophobic Interactions and Hydrogen Bonding at the Target-Ligand Interface Leads the Pathways of Drug-Designing

Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds.In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy.The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy

Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use

Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a “resistant” variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching

Optical signatures of molecular dissymmetry: Combining theory with experiment sestereochemical Puzzles

Modern chemistry emerged from the quest to describe the threedimensional structure of molecules: van't Hoff's tetravalent carbon placed symmetry and dissymmetry at the heart of chemistry. In this Account, we explore how modern theory, synthesis, and spectroscopy can be used in concert to elucidate the symmetry and dissymmetry of molecules and their assemblies. Chiroptical spectroscopy, including optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA), measures the response of dissymmetric structures to electromagnetic radiation. This response can in turn reveal the arrangement of atoms in space, but deciphering the molecular information encoded in chiroptical spectra requires an effective theoretical approach. Although important correlations between ECD and molecular stereochemistry have existed for some time, a battery of accurate new theoretical methods that link a much wider range of chiroptical spectroscopies to structure have emerged over the past decade. The promise of this field is considerable: theory and spectroscopy can assist in assigning the relative and absolute configurations of complex products, revealing the structure of noncovalent aggregates, defining metrics for molecular diversity based on polarization response, and designing chirally imprinted nanomaterials. The physical organic chemistry of chirality is fascinating in its own right: defining atomic and group contributions to optical rotation (OR) is now possible. Although the common expectation is that chiroptical response is determined solely by a chiral solute's electronic structure in a given environment, chiral imprinting effects on the surrounding medium and molecular assembly can, in fact, dominate the chiroptical signatures. The theoretical interpretation of chiroptical markers is challenging because the optical properties are subtle, resulting from the strong electric dipole and the weaker electric quadrupole and magnetic dipole perturbations by the electromagnetic field. Moreover, OR arises from a combination of nearly canceling contributions to the electronic response. Indeed, the challenge posed by the chiroptical properties delayed the advent of even qualitatively accurate descriptions for some chiroptical signatures until the past decade when, for example, prediction of the observed sign of experimental OR became accessible to theory. The computation of chiroptical signatures, in close coordination with synthesis and spectroscopy, provides a powerful framework to diagnose and interpret the dissymmetry of chemical structures and molecular assemblies. Chiroptical theory now produces new schemes to elucidate structure, to describe the specific molecular sources of chiroptical signatures, and to assist in our understanding of how dissymmetry is templated and propagated in the condensed phase. © 2009 American Chemical Society