Any approach applied to drug discovery and development by the medical community and pharmaceutical industry has a direct impact on the future availability of improved, novel, and curative therapies for patients with cancer. By definition, drug discovery is a complex learning process whereby research efforts are directed toward uncovering and assimilating new knowledge to create and develop a drug for the purpose of providing benefit to a defined patient population. Accordingly, a highly desirable technology or approach to drug discovery should facilitate both effective learning and the application of newly discovered observations that can be exploited for therapeutic benefit. However, some believe that drug discovery is largely accomplished by serendipity and therefore appropriately addressed by screening a large number of compounds. Clearly, this approach has not generated an abundance of new drugs for cancer patients and suggests that a tangibly different approach in drug discovery is warranted. We employ an alternative approach to drug discovery, which is based on the elucidation and exploitation of biological, pharmacological, and biochemical mechanisms that have not been previously recognized or fully understood. Mechanism-based drug discovery involves the combined application of physics-based computer simulations and laboratory experimentation. There is increasing evidence that agreement between simulations based on the laws of physics and experimental observations results in a higher probability that such observations are more accurate and better understood as compared with either approach used alone. Physics-based computer simulation applied to drug discovery is now considered by experts in the field to be one of the ultimate methodologies for drug discovery. However, the ability to perform truly comprehensive physics-based molecular simulations remains limited by several factors, including the enormous computer-processing power that is required to perform the formidable mathematical operations and data processing (e.g. memory bandwidth, data storage and retrieval). Another major consideration is the development of software that can generate an appropriate and increasingly complex physical representation of the atomic arrangements of biological systems. During the past 17 years, we have made tremendous progress in addressing some of these obstacles by developing and optimizing physics-based computer programs for the purpose of obtaining increasingly accurate and precise information and by improving the speed of computation. To perform physics-based simulations that involve complex systems of biological and pharmaceutical interest, we have developed methods that enable us to exceed Moore's law. This has been accomplished by parallel processing as well as other methods that have enabled us to study more complex and relevant molecular systems of interest. This paper provides an overview of our approach to drug discovery and describes a novel drug, currently in clinical development, which has directly resulte...

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The GGT xenobiotic metabolism pathway is postulated to be a major toxification pathway for cisplatin nephrotoxicity, and BNP7787 may play a novel and critical therapeutic role in the modulation of GGT activity. We further postulate that there are two general mechanisms for BNP7787-mediated nephroprotection against cisplatin-induced nephrotoxicity involving this pathway. First, the active BNP7787 pharmacophore, mesna, produces an inactive mesna-cisplatin conjugate that is not a substrate for the GGT toxification pathway (GGT xenobiotic metabolism pathway) and, second, BNP7787-derived mesna-disulfide heteroconjugates may serve as selective, potent inhibitors of GGT, possibly resulting in nephroprotection by a novel means.

BNP7787-mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve APN inhibition by certain BNP7787-derived mesna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for BNP7787-mediated nephroprotection of cisplatin-induced nephrotoxicity involving the GGT, APN and CCBL nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity.

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