Difficulties implementing denovo design

Difficulties implementing denovo design

Many of the worlds largest pharmaceutical firms spent millions of dollars on hardware and software in their endeavor to make denovo design a reality. Unfortunately, successes were rare. Except for a few exceptions, denovo design was an utter failure, and did not prove to be an effective method to discover lead compounds. The main reasons were limitations in computing power and the lack of useful software functionality. In scientific computing, accuracy and processing time are always a tradeoff. Thus, in order to make the calculations run in a finite period of time, a plethora of assumptions, significant approximations, and numerous algorithmic shortcuts had to be utilized. This, in turn, greatly diminished the calculated accuracy of any ligand receptor interaction. As such, chemists could postulate numerous chemical structures that could potentially complement the active site; however, the calculated binding had no correlation with reality.

This remains the most significant challenge in denovo design to this day. Although computers have become exponentially faster, the sheer number of calculations needed to accurately predict the binding of a denovo generated ligand to its receptor in a useful timeframe still requires significant approximations. In denovo design, we are attempting to generate a whole ligand from scratch and dock it within the receptor. As stated above, the difficulty lies in predicting how the chemical structure will behave in real life. A ligand is an inherently flexible structure, and can assume a plethora of different conformations and orientations. The big question remains whether the predicted binding structure will mirror the calculated one. Failure in this endeavor has undermined the utility of denovo structure generating software. We will discuss these shortcomings and the technological advances of RACHEL, which attempt to circumvent these deficiencies, in detail below.

The second most significant problem in computer aided denovo design is the generation of undesired chemical structures. There are a nearly infinite number of potential combinations of atoms. However, the vast majority of these structures are of no use. As discussed above, undesired structures are rejected due to toxicity, chemical instability, or synthetic difficulty. Nearly all denovo design software packages are plagued by this problem, especially with respect to synthetic feasibility. Thus, although such software can postulate potential complementary ligands, the vast majority of them are worthless. We will discuss in great detail below how RACHEL attempts to circumvent this problem with newly developed technology.

The end result of these shortcomings was that computer aided denovo design soon fell out of favor as a means of generating viable lead compounds. By the mid 1990’s there had been a tremendous number of denovo software packages released; however, they all suffered these same problems. Gradually, such programs were shelved and investigators looked to other technologies to aid in their drug development efforts.

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