Pneumocystis carinii pneumonia is a major concern in the treatment of AIDS patients and transplant surgery patients. Current approaches to the treatment of this opportunistic infection are aimed at the inhibition of P. carinii dihydrofolate reductase (DHFR). These treatment regimens utilize the antifolate, trimethoprim in combination with a sulfonamide. This regimen illicits inadequate results due to the observed high levels of toxicity and to the very poor inhibitory effect of trimethoprim on the P. carinii DHFR. An alternative treatment strategy has been more recently introduced which employs the anti-folates trimetrexate and piritrexim. These agents are better DHFR inhibitors, but their lack of specificity allows them to also inhibit the human DHFR, thereby causing significant toxicity to human cells. Consequently, the need for a treatment regimen specific for P. carinii pneumonia continues to go unanswered. Since anti-folates bind DHFR at the folate binding site, the major of this proposal is to design agents which can successfully discriminate between the P. carinii and human DHFR folate binding sites and preferentially bind to and inhibit the P. carinii DHFR. It is proposed to achieve this goal by using interactive computer assisted molecular modeling and drug design. These methods will employ the three- dimensional P. carinii DHFR folate binding site model and X-ray determined structure of the human DHFR folate binding site. New agents will then be designed whose chemical structures maximally bind to the P. carinii folate binding site and minimally bind to the human DHFR binding site. In this manner new agents which are specifically inhibitory to the P. carinii DHFR will be obtained. This project introduces a new methodology for the design of effective therapeutic agents with minimal toxicity. This drug-design project is related to a separate and subsequent project which will involve the subsequent chemical synthesis of any newly designed agents via collaborations with organic chemists. Also, as a part of that separate project, the resulting synthesized agents will be subjected to biochemical and pharmacological evaluation via collaborations with biochemists and pharmacologists. The two projects combine to form a comprehensive drug development effort. However, it should be noted that funds are only requested for the computer assisted drug design project.
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