The biological activity of oxoformycin B has been exafned on the basis of the model developed for the incorporation of nucleoside analogues during transcription. Claverie’s simplified formula has been employed for intermolecular interaction energy calculation. The pairing energy of oxoformycin B base with complementary bases as well as the association energy with nucleic acid base pairs have been calculated. The results are compared with those of similar computation with normal bases. In addition to the in-plane interaction the vertical interaction energy between the analogue and the normal bases has been computed to specify the particular position of the analogue in the chain. On the basis of the model an attempt has been made to explain the mechanism of the biological action of oxoformycin B and to compare the biological activity of pyrazolopyrimidine nucleoside analogues.

The quantum mechanical perturbation method has been utilized to study the biological activity of 8-azapurine (8-azaguanosine, 8-azaadenosine and 8-aza-2,6-diamino-purine) nucleoside antibiotics. The in-plane (hydrogen bonding) and stacking energy of 8-azapurine bases have been evaluated with nucleic acid bases and base pairs in all possible orientations. The energy values and the sites of association of analogous bases, obtained by optimization of energy values as well as the sites of association of nucleic acid bases during the transcription process have been compared. The model developed earlier for the incorporation of nucleoside analogues has been used to find out the inhibitory effects of the drug on nucleic acid and protein synthesis. It has been observed that the activity of 8-azapurines are of the following order

8-azaguanine > 8-aza-2,6-diaminopurine > 8-azaadenine

and these analogues show preference for binding near a guanine or cytosine in the chain. The results are in agreement with the experimental observations

CaMDR1 encodes a major facilitator superfamily (MFS) protein inCandida albicans whose expression has been linked to azole resistance and which is frequently encountered in this human pathogenic yeast. In this report we have overexpressed CaMdr1p inSf9 insect cells and demonstrated for the first time that it can mediate methotrexate (MTX) and fluconazole (FLC) transport. MTX appeared to be a better substrate for CaMdr1p among these two tested drugs. Due to severe toxicity of these drugs to insect cells, further characterization of CaMdr1p as a drug transporter could not be done with this system. Therefore, as an alternative, CaMdr1p and Cdr1p, which is an ABC protein (ATP binding cassette) also involved in azole resistance inC. albicans, were independently expressed in a common hypersensitive host JG436 ofSaccharomyces cerevisiae. This allowed a better comparison between the functionality of the two export pumps. We observed that while both FLC and MTX are effluxed by CaMdr1p, MTX appeared to be a poor substrate for Cdr1p. JG436 cells expressing Cdr1p thus conferred resistance to other antifungal drugs but remained hypersensitive to MTX. Since MTX is preferentially transported by CaMdr1p, it can be used for studying the function of this MFS protein.