Supercomputer Aided Drug Design: Application in Oncology and AIDS

Abstract

Significant advancements in the treatment of cancer have developed during the last four decades as a result of dedicated clinical and experimental efforts. Many of the therapeutic gains are related to discovery and development of more effective medicinal agents, technologic advancements, and an enhanced understanding of the fundamental chemical and biologic interactions involving the pathogenesis and pathophysiology of these heterogenous diseases. It is now possible to cure several types of malignancy and to achieve significant palliation in a variety of other tumors. Unfortunately, many of the more common types of neoplasms (e.g. carcinomas of the lung, breast, GI tract, and melanoma) are refractory to therapy with currently available agents. A most significant obstacle to address in the coming years is multiple drug resistance in which the cytotoxic action of pharmacologic agents is rendered ineffectual by a transmembrane pump in tumor cells (1–3). Early in this past decade, infection with the human immunodeficiency virus (HIV) has presented a major health problem because of the lethal nature of the disease, significant latent interval between infection and disease manifestation, fluctuating/ evolving epidemiologic patterns, and the lack of effective therapy. An important complication of pharmacologic agents that must be considered in the development of new therapeutic agents for the AIDS and neoplastic disorders are the immediate and long term clinical toxicities that frequently affect the quality of life (4). Because of the immediate and life-threatening nature of these diseases the untoward effects of these agents have been monitored and managed expectantly, since some toxicities can be lethal to the patient. Our primary research is directed towards generating new classes of pharmacologic agents possessing highly specific cytotoxicity for neoplastic cells, and cells that have incorporated the HIV genome. The major goals of developing such agents will be to cure these diseases which are currently refractory to therapy with minimal patient toxicity.