Chemical databases are becoming a powerful tool in drug discovery. Database searches based on possible requirements for biological activity can identify compounds that might be suitable for further analysis or indicate novel ways to achieve the desired activity. What considerations are involved in the construction and searching of chemical databases?
The evolutionary conservation of DNA polymerase alpha was assessed by immunological and molecular genetic approaches. Four anti-human KB cell DNA polymerase alpha monoclonal antibodies were tested for their ability to recognize a phylogenetically broad array of eukaryotic DNA polymerases. While the single non-neutralizing antibody used in this study recognizes higher mammalian (human, simian, canine, and bovine) polymerases only, three neutralizing antibodies exhibit greater, but variable, extents of cross-reactivity among vertebrate species. The most highly cross-reactive antibody recognizes a unique epitope on a 165-180 kDa catalytic polypeptide in cell lysates from several eukaryotic sources, as distant from man as the amphibians. Genomic Southern hybridization studies with the cDNA of the human DNA polymerase alpha catalytic polypeptide identify the existence of many consensus DNA sequences within the DNA polymerase genes of vertebrate, invertebrate, plant and unicellular organisms. These findings illustrate the differential evolutionary conservation of four unique epitopes on DNA polymerase alpha among vertebrates and the conservation of specific genetic sequences, presumably reflective of critical functional domains, in the DNA polymerase genes from a broad diversity of living forms.
to that of a hydrogen atom. Thus, it may be that no "rules" are violated in interpreting the greater cleavage of P-Cl bonds by an inversion route compared to cleavage of P-F bonds.That the two forms, B and C, might arise in competition with each other in the first place most likely rests with a balance of relief of a certain degree of ring strain for the six-membered form favoring intermediate C. As M a r~i~'~~~ has shown in the alkaline cleavage of cyclic phosphonium salts varying in ring size from five to seven membered, the stereochemistry goes from 100% retention for reaction of a fivemembered ring cis-phosphonium salt, to about 50% retention for reaction of the corresponding six-membered ring cis-phosphonium salt, and to 0% retention for reaction of the seven-membered ring salt, all with cleavage of the poor leaving group, benzyl. Activated-state E may result as a kinetically favored initial intermediate if we assume that the a-naphthyl group is of sufficient size to sterically block the approach of the nucleophile opposite the endocyclic S i 4 bond undergoing cleavage. Pseudorotation then brings the Si-0 bond to a departing apical position. Intermediate D may gain relative stability to E with the use of a softer nucleophile. In addition to the relief of ring strain, hydrogen bonding may assist in the cleavage process as indicated in D.
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