The role of the medicinal chemist in drug discovery

The Role of the Medicinal Chemist in Drug Discovery

Medicinal chemists are crucial in preparing and selecting compounds for biological evaluation. If these compounds prove to be active, they serve as lead compounds. Evaluating the structure-activity relationships (SARs) of similar compounds concerning their in vitro and in vivo efficacy and safety is also a key part of their role. Nowadays, medicinal chemists are part of interdisciplinary teams, requiring knowledge not only in organic chemistry but also in other scientific domains to anticipate and resolve problems and interpret developments effectively.

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The role of the medicinal chemist has evolved dramatically over the past 25 years. From the 1950s to about 1980, chemists primarily relied on in vivo testing data. However, the introduction of new technologies like high-throughput in vitro screening, large compound libraries, combinatorial technology, defined molecular targets, and structure-based drug design has changed the landscape since the 1980s. While these technologies offer new opportunities, they also present new challenges, including increased safety requirements and complexities in translating in vitro activity to in vivo activity. Additionally, the complexity of demonstrating clinical safety and efficacy in humans has significantly increased, requiring extensive data and understanding in various domains.

The cost and duration of drug discovery and development have also escalated, with estimates putting the cost at around $1.4 billion for a single new drug. Only a fraction of the scientific hypotheses lead to a drug candidate, and an even smaller number become marketed products. Despite the high stakes and risks, the role of the medicinal chemist remains essential, especially in the early phases of drug discovery.

The Process of Drug Discovery

Inventing and developing a new medicine involves a long, intricate, costly, and risky process. Research and development (R&D) can take anywhere from 12 to 24 years for a single medicine, from project initiation to product launch. Many research projects fail to produce marketable medicines, and the cost for this process has escalated to an estimated $1.4 billion per drug. Only about 1 out of 15-25 drug candidates progress through the rigorous animal and human testing phases to become marketed products. Moreover, only one in three will become a major commercial success.

The drug discovery process starts by identifying a medical need and evaluating existing therapies. Following this, hypotheses on how to improve therapy are formed. Objectives are then set for the project, and selected chemicals undergo biological testing. Subsequent steps include detecting relevant biological activity (in vitro), identifying a compound with in vivo activity in an animal model, preparing analogous structures, and selecting one compound as the drug development candidate. This candidate undergoes toxicological testing in animals as required by law before submitting an Investigational New Drug Application (IND) to the FDA. Clinical trials follow in three phases to evaluate toleration, efficacy, and safety before a New Drug Application (NDA) is filed for FDA review.

The Role of the Medicinal Chemist Today

The modern medicinal chemist plays a vital role in the early drug discovery phases. Trained to prepare new chemicals and armed with knowledge of the target disease and competitive therapies, the chemist frames the hypothesis and sets project objectives. The chemist also decides which chemicals to screen for lead compounds and synthesizes hits for biological evaluation. Developing in vivo activity for hit compounds, overcoming ADME (absorption, distribution, metabolism, and excretion) challenges, and maximizing efficacy while minimizing side effects fall under the chemist's responsibilities.

Today's medicinal chemists require various skills, including modern organic and medicinal chemistry knowledge, an understanding of target disease biology, familiarity with pharmacological tests, and awareness of clinical, regulatory, and competitive landscapes. Superior interpersonal skills are also essential for effective collaboration with interdisciplinary colleagues.

Despite some differences from earlier drug discovery eras, medicinal chemists face many of the same tasks and challenges today. They continue to select structural series of compounds and pursue SARs to identify suitable drug candidates for advancement to safety and clinical testing. However, modern chemists have more advanced tools, including improved synthetic, analytical, and purification technologies, computer-assisted literature and data retrieval, and combinatorial chemistry and high-throughput screening.

In the contemporary drug discovery model, molecularly defined biological targets like enzymes, receptors, and transporters play a significant role. The use of defined molecular targets facilitates structure-based drug design, allowing chemists to design new compounds by visualizing their interactions with target proteins through X-ray crystallographic analysis.

Advancements in addressing pharmacokinetic issues, such as in vitro screens predictive of human pharmacokinetics, permeability, and transporter assays, further aid today's chemists in characterizing drug uptake and efflux. Predicting and synthesizing "drug-like" compounds with favorable properties, guided by the 'rule-of-five' formulated by Lipinski et al., helps chemists optimize compound selection.

In addition to efficacy and pharmacokinetics, toxicity screening is crucial in the drug discovery process. Modern chemists utilize various in vitro toxicity screens, including the Ames test for mutagenicity and the hERG channel assay for cardiac safety, to weed out unsafe compounds early in development.

Recent Changes in Medicinal Chemistry

Today's medicinal chemists live in exciting times, playing a crucial role in developing more selective, effective, and safer medicines. However, productivity in drug discovery has not kept pace with increasing resource allocation. To improve the drug discovery process, coordinating animal testing with in vitro testing early in the process, appointing a small, permanent committee to oversee drug development, and passing on the tacit knowledge of experienced chemists to the next generation through in-house workshops and lectures are suggested strategies.

The pharmaceutical industry has evolved significantly, with a shift from highly autonomous individual chemists to collaborative interdisciplinary teams influenced by business units. Despite these changes, the role of serendipity, chemical intuition, and creativity in discovering quality drugs remains undiminished.

Medicinal chemists today are key participants in producing more selective, effective, and safer medicines to treat diseases. Their work can significantly benefit millions of patients, providing a powerful motivation for any scientist.

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