Overcoming Key Challenges in Drug Discovery

Computer-aided Synthetic Design (CASD) may have been born out of the work of E.J. Corey et al. in the 1960s, but only in the twenty-first century has it begun to transform chemical synthesis. SYNTHIA™ Retrosynthesis Software is leading this effort by combining powerful artificial intelligence (AI) with expert-coded chemical synthesis rules.

Drug discovery is a risky endeavor 

It can take up to 12 years or more to bring a new pharmaceutical to market with costs that can exceed $2.6 billion. Developing pharmaceutical compounds is a lengthy, iterative process that requires sifting through thousands of molecular targets to find the right candidate. This arduous process requires countless experiments across multiple research and development departments.

Researchers usually begin by screening libraries that contain tens of thousands of compounds. With the assistance of high-throughput assays and computer software, the team may uncover a small number of initial hits. Medicinal chemists then begin modifying the core chemical structure to alter both physical & chemical properties, adding or subtracting molecular components to tease out effects that may improve drug characteristics. 

A battery of tests is used to determine the suitability of each candidate as a bio-active pharmaceutical. Only the compound with the best therapeutic efficacy and safety profile will make it to market. During this process, the feasibility of large-scale synthesis and, ultimately, manufacturing of the compound is also explored. Only then is the drug ready for testing in pre-clinical studies before ultimately being introduced into clinical trials.

Unfortunately, only a few compounds reach clinical trials.

Is drug discovery sustainable?

Central to drug discovery is small molecule chemical synthesis, involving a complex, step-by-step process whereby teams of chemists produce purpose-built novel molecules. This remains to be a significant bottleneck for advancing new medicines to clinical trials despite over a century of advancements in synthetic chemistry technology.

Historically, synthetic chemistry has relied on the knowledge and expertise of highly trained synthetic organic or medicinal chemists, who were responsible for designing both novel molecules and the complex routes to synthesize them without advanced decision support tools. Recent advances in AI may now improve outcomes and accelerate drug discovery projects. With CASD, the modern, sophisticated researcher can bring more targets to market more sustainably. 

However, it’s no longer enough for a chemical synthesis to achieve sustainability only from an economic standpoint. Greener, safer, and more eco-conscious chemistry has been a topic of global importance for the last 50 years. Yet, only in the last 25 years have chemists had access to a clear set of guidelines, known as the 12 Principles of Green Chemistry, developed by Anastas & Warner. Still, there have been few tools available to the research chemist that provide decision support to enable achieving these noble initiatives. 

MilliporeSigma’s head of Cheminformatics, Ken Karapetyan, PhD, weighs in on the role that computer-aided synthetic design has in corporate sustainability:

“With society growing more aware of corporate sustainability, corporations are reevaluating their social responsibility. This is driving organizations to switch the consumption of electricity, for example, to renewable alternatives, or arranging smart sustainable offices. Many chemical research organizations introduce sustainability in procuring building blocks to address poor atom economy. This is common in pharmaceutical research, where the goal is to synthesize a wide range of diverse compounds quickly and reliably. SYNTHIA™ can greatly help in reevaluating an organization’s synthetic chemistry footprint (e.g. manufacturing and drug design) by introducing atom efficiency for scoring the alternative pathways, thus making chemical manufacturing more efficient.”

Retrosynthesis is a creative process that is hard to engineer

Retrosynthetic analysis has been taught as a bond-disconnection strategy in advanced organic chemistry courses for nearly 50 years. For many chemists, it is a creative problem-solving technique that is a “badge of honor” when an imagined synthetic route is tested and validated. This process relied only on the chemist’s personal knowledge and the simple tools of a pencil and paper. However, the demands of modern drug discovery have pushed the research chemist to harness the power of cheminformatics to positively augment their chemical intuition and expand the realm of possible disconnections using software. 

Today, researchers find they can super-charge their brainstorming process and spark more creative and imaginative solutions using computer-aided synthetic planning. Whereas the “old way” of synthetic planning was limited by the individual background expertise within a group, the “new way” empowers individual researchers to be more creative while still allowing for group collaboration in a virtual space.

The flexibility of a retrosynthesis tool like SYNTHIA™ appeals to both the creative and practical aspects of synthesis design. This duality of features is what makes the power of computer-aided synthetic planning so appealing and beneficial to a broad range of chemical researchers.

“We see more and more scientists desire to use CASD to get insights on possible alternative retrosynthetic pathways,” explains Karapetyan. “Those scientists are mostly within the R&D drug discovery organization as synthetic chemists and medicinal chemists. Process chemists, who are focused on optimizing and scaling up the existing synthetic routes, have also found SYNTHIA™ useful to provide insights on alternative retrosynthetic pathways.”

Coded by chemists and computer scientists for more than 15 years, SYNTHIA™ Retrosynthesis Software is powered by sophisticated algorithms that can help experts easily access decades of chemical research data.

SYNTHIA™ Retrosynthesis Software reduces risk, supports sustainability, and enables ingenuity

Computer-aided synthesis planning has become more than an academic curiosity. Implementing this technology into drug discovery workflows is accelerating development of therapeutic targets and clearly increasing in usage. Since 1995, more than 1,000 scientific publications include “computer-aided drug design” in the title or abstract and of those, more than 40 percent were from the last five years. 

According to Karapetyan, “There are a growing number of computational drug discovery platforms where vendors create an end-to-end experience to produce virtual drug candidates for specific targets. SYNTHIA^TM then can integrate with those platforms via API and do a tremendous job of filtering out virtual compounds that are not easily synthesizable.”

SYNTHIA™ provides valuable insights by leveraging advanced algorithms combined with more than 100,000 expert-coded organic chemistry reaction rules. 

“It is very hard to keep all relevant synthesis knowledge operational in your mind and then be able to apply it on-demand. By using SYNTHIA™, researchers can easily gain insights on alternative routes. However, we do believe that chemists must know the alternatives before designing a synthesis as it lowers the risk of missing an important, cost-effective pathway that could have a big cost implication for the organization,” says Karapetyan.

Most small molecule drugs are the end-product of painstaking laboratory work —the result of an intricate process of hypothesis, design, and synthesis of individual molecules and testing their effects in biological systems. SYNTHIA™ can significantly speed up this process, accelerating drug discovery so that people can benefit from new life-changing medicines sooner.

To contact SYNTHIA™ Support, find out more, or request a demo please click HERE.