Why all these brilliant molecules don’t become drugs?
Professor Marcin Kołaczkowski, a leading expert in medicinal and computational chemistry at the Jagiellonian University Medical College, will explore a fundamental question in drug development: “Why don’t all these brilliant molecules become drugs?” Drawing on over two decades of experience in research and collaboration with the pharmaceutical industry, he will discuss the complex path from laboratory discoveries to real-world therapies. The seminar will shed light on the many challenges that stand between innovation and approved treatments, offering valuable insights into the realities of modern drug discovery.
This video is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) license. You are free to share it for non-commercial purposes with proper attribution, but no modifications or adaptations are allowed.
1. Why use this method?
Drug discovery and development (DDD) is one of the most challenging yet deeply rewarding scientific processes. The complexity of the task is evidenced by the fact that over 90% of DDD projects ultimately fail, which underscores the need for a systematic and rigorous approach. Therefore, successful development of a medicine demands operating in the pharmaceutical context from very early stages of the project – this includes clearly defining the drug’s intended purpose, adhering to the guidelines of regulatory agencies, and addressing legal and financial requirements from the start.
2. What you’ll need
To properly execute a drug discovery and development project you must consider several factors:
- Medical need – your drug candidate must address a genuine medical need. It requires consultations with the clinicians, rather than relying solely on existing literature.
- Science – your novel compound should possess scientific foundation. You should have comprehensive knowledge regarding its mechanism of action and other properties.
- People/ technology/ infrastructure – you need appropriate resources to execute your project, including highly specialized personnel, advanced technology and adequate infrastructure.
- Intellectual property protection (IP) – to ensure potential profitability, your novel drug candidate must be protected through patents or other measures of IP protection.
- Competition appraisal – you need to assess the risk of other laboratories achieving similar scientific and technological advancements. Maintaining a competitive edge is necessary to make profit.
- Money – drug discovery and development is aa substantial financial undertaking. To gain investment, your proposed project needs to be profitable.
- Market size – your drug must be useful to a sufficiently large patient population to attract investments.
3. Step-by-step instructions
Drug discovery and development workflow:
- High-throughput screening – determine the IC50 of your screened compounds and conduct hit triage.
- Hit to lead – perform selectivity assays, in vitro evaluations and Tier I ADME/ physicochemical assays to identify hit compounds.
- Lead optimization – conduct in vivo assays along with Tier II ADME/ physicochemical assays to refine lead compounds.
- Candidate selection – assess whether the lead compound demonstrates a satisfactory combination of efficacy, safety, physicochemical, pharmacokinetic, and toxicological properties. Additionally, consider synthesis scalability, patentability and competitive advantage. If all these criteria are met, the compound can advance to the pre-clinical development stage.
- Pre-clinical development – develop bioanalytical methods under both GLP and non-GLP conditions. Implement CMC (Chemistry, Manufacturing and Controls) which includes production of “tox batch” and “clinical batch” under GMP standards, establish scalable synthesis processes. Conduct GLP-compliant toxicology studies (in vivo studies in two species), genetic toxicology, safety pharmacology, and extended pharmacokinetic evaluations. Finally, prepare the protocol for the initial clinical trials.
- Clinical development:
- Phase I – evaluate safety and tolerability in healthy volunteers.
- Phase II – assess safety, tolerability and early clinical proof of principle (POP).
- Phase III – conduct large-scale trials to establish definitive POP.
- Regulatory approval – obtain authorization to bring the drug candidate to market following comprehensive regulatory review.
4. Practical tips
- Focus on value of your project – your drug candidate must promise high therapeutic benefit with a favorable cost x risk profile. Investors fund products that are financially attractive and meet a real medical need.
- Secure intellectual protection early – patentability and market exclusivity are critical. Without strong IP protection, your project will not be possible.
- Start with the end goal in mind: align your early DDD processes with regulatory, legal, and financial requirements.
- Don’t rush into in vivo studies – before moving to animal testing, understand well mechanism of action of your compound, confirm a therapeutic window, and consider administration route.
- Take care of your data – ensure that your results are reproducible and properly documented.
5. Critical appraisal & implications for future research
Drug discovery is a complex multifactorial process that requires many more steps than simply demonstrating biological activity of the selected chemical compound. While activity remains a key criterion, it must be evaluated alongside other factors such as safety, pharmacokinetics, developability, and regulatory compliance. A thorough understanding of the clinical context and the practical aspect of pharmaceutical development is essential from the early stages of a project.
Failures in drug development can often stem from neglect of key non-scientific elements such as lack of IP protection, reliance on poorly translatable animal models, or insufficient consideration of manufacturing and scalability. Overlooking these factors can compromise securing funding or hinder regulatory approval. Future research should aim to help scientists in integrating scientific breakthroughs with regulatory and translational awareness. This includes designing experiments with clinical relevance, thoroughly documenting results, and aligning the project with industry and investor expectations. That way promising compounds will get a real chance to successfully progress through the drug development pipeline.
This protocol is licensed under a Creative Commons Attribution-NonCommercial (CC BY-NC) license, allowing sharing and adaptation for non-commercial purposes with proper attribution.
Send a message

Adding comments is only possible for registered users.
Sign in