Enabling Synthetic and Medicinal Chemists with the Predictive Power of Quantum Mechanics

Innovation That Matters

By Rich Soll (Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx).

A key rate-limiting step in the discovery of drugs is the synthesis of target molecules:  multistep, many times low yielding, many times taking weeks to prepare a single molecule. Often, side reactions result in unanticipated products or the desired reaction product is not realized. This is particularly true for heterocyclic systems where the introduction of a single heteroatom into a structure, such as nitrogen, can be not only synthetically challenging, but also, many times it alters reactivity in a quite unexpected or non-obvious manner.

John Wai, Vice President Medicinal Chemistry at WuXi AppTec and American Chemical Society Heroes of Chemistry awardee, commented: “This has been, and continues to be, a significant hurdle in our industry, especially when you consider that it takes typically in the order of 1,000 candidates over several years to achieve a candidate worthy to advance into clinical trials. A key bottleneck, the synthesis of each candidate, then becomes a limiting factor.”

“Synthetic chemists are taught to analyze chemistry in a very intuitive way. Powerful, but it has its limitations,” asserted Wai.  “Application of quantum mechanics (QM) in the synthetic setting allows us to break this limitation and to critically examine the molecular orbital features of the reactants that may govern a particular reaction; it allows us to think in a much deeper and fundamental manner.”

John and his team at WuXi use the commercially available program Spartan. Advances in computing power have dramatically accelerated the rate at which calculations are generated. The team calculated and analyzed the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), as well as the electrostatic potential map and LUMO map. The team augmented the analysis with computationally-generated 13C-NMR shifts and in some cases, the IR spectra. In the event where a deeper understanding was needed, reaction energy profiles and transition states calculations, which were more computationally intensive, were undertaken to better understand the reaction mechanism.

How then does this technology enable synthetic and medicinal chemists?  “Many different types of reactions, such as electrophilic aromatic substitution, the Pictet-Spengler reaction, Diels-Alder reaction, Claisen Condensation, Fischer Indole synthesis, 2+3 cycloaddition, and many others are extensively examined,” noted Wai.  “Chemists are routinely using the technology for synthetic planning, predicting regioselectivity, rationalizing side product appearance, and determining reactivity. The chemists are finding that the use of QM is decreasing failed reaction frequency, while increasing rates of success in terms of yields and time spent on a particular reaction, amongst other considerations.”

The insights from QM, gleaned from small molecule chemistry, have been applied to macro-molecular problems such as antibody drug conjugates. Specifically, Wai cited a long-standing challenge of thio exchange to effect the necessary level of conjugation. “Previous work resulted in drug-antibody ratio of about 0.6 (vs an optimum of two with two cysteines on the antibody).  The WuXi team used LUMO calculations to guide them to look for a much better leaving group.  This improved the conjugation effect and drug-antibody ratio to 1.9, a result of significant potential.”

“We teach and set up workshops for chemists across different levels of expertise,” noted Wai.  “We want chemists to think deeply about their chemistry and to incorporate the technology into their daily planning.  Although it is still an expert system, we are finding that synthetic chemists who use these tools can increasingly tackle more complex chemistry and solve more problems more accurately.”

Chemists now have more effective and data-driven guides to improve chemical processes, to reduce side reactions and avoid dead-ends, particularly as the drug candidates are getting increasingly complex.  Further, the same principles learned from one system can be applied to other heterocyclic systems, including ones never synthesized or reported in the literature before.

Wai took QM and his insights on the road to broadly enable WuXi’s customers and the global synthetic and medicinal chemistry communities in advocating and implementing desktop QM computing. Over the last 18 months, Wai delivered two seminars for the Boston drug discovery community and presented more than half a dozen seminars at global partners and at major global institutes.

Looking forward, Wai is excited. “The time has arrived where computational technology is impacting synthetic design; the more people using it, the more experience and insights will be gleaned from it.  This knowledge and information makes for better chemists, which then becomes enabling for our partners. It is spectacular to see WuXi contributing to this. In the end, we hope these advances are fundamental to the success of our customers and, ultimately, to the effective and faster delivery of better medicines to patients.”

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