Umar Akbar.

Graduate Student
University of California, Berkeley

B.S. Chemical Engineering, 2001
Cornell University
Office Location: 497A Tan Hall
Office Telephone: 643-8340
Office Fax: 643-1228

Solid Phase Combinatorial Biocatalysis of Indinavir

My research thesis involves applying solid-phase synthesis to the emerging field of combinatorial biocatalysis, a technique used to rapidly and efficiently optimize pharmaceutical lead compounds. Since combinatorial chemistry, the method currently used to generate pharmaceutical leads, is geared primarily towards lead compound discovery rather than optimization, the initial lead compounds developed by this method typically lack several desired pharmacokinetic properties such as reaction selectivity, high potency and bioavailability, and reduced toxicity. Normally, the various methods of combinatorial biocatalysis are carried out in solution. However, in this particular study, we are hoping to couple the exquisite and controllable selectivity and unique reactivity of biocatalysis with the high-throughput features of solid phase techniques to provide a more direct route towards synthesizing phramacokinetically-optimized compounds. In particular, solid-phase synthesis would confer the following process advantages:

1. Simplified purification

2. Enabling of excess reagents to drive reactions

3. Avoiding limitations of substrate solubility

4. Ease of handling on small scales.

In short, the ability to quickly and efficiently create new derivatives from promising lead compounds will help overcome a major bottleneck of drug discovery - namely the difficulty involved with generating biologically active and diverse derivatives from complex lead molecules. Therefore, the development of this technology could represent a major advance in drug discovery and development by enabling the synthesis of new compounds on solid supports via solid-phase combinatorial biocatalysis.

Indinavir has been chosen as the model compound for this study for both chemical and practical reasons. Structurally, Indinavir is an optimal compound for solid-phase biocatalysis due to its structural complexity, the presence of multiple functional groups, and the presence of suitable sites for attachment to a solid support. However, the primary reason for the choice of Indinavir as the lead compound for combinatorial biocatalysis is its pharmacological importance, particularly as a newly developed HIV-1 protease inhibitor as part of a treatment regimen for AIDS, as well as the availability of an activity screen using HIV protease. Thus, while the primarily goal of this research will be to develop solid-phase combinatorial biocatalysis as a general drug discovery technique, an important secondary objective will be to discover optimized derivatives of the lead compound, Indinavir. Furthermore, the specific goals of this research project are as follows:

1. Identify techniques for attaching complex, multifunctional lead compounds onto solid supports via both chemical and chemoenzymatic selective attachment/detachment procedures.

2. Develop soluble enzyme systems for derivatization of solid supported compounds, including solubilized enzymes for use in organic media as well as the preparation of microbial extracts to access a wide range of biocatalytic activities.

3. Elucidate the effects of diffusion, linker and solvent on the reactivity of solid-supported substrate.

4. Employ combinatorial biocatalysis techniques to derivatize lead compounds attached to solid supports - this aspect represents one of the core aims of the Clark research group during the previous decade.