Did you know the multiple usage of small molecules?

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2021 marks the 125th anniversary of the Bayer Chemical Research Laboratory in Wuppertal, Germany. Many famous small-molecule drugs, from aspirin to rivaroxaban, have emerged from the research station.Small molecules continue to enable medical breakthroughs and address medical needs, saving countless lives. Small molecules play a vital role as chemical probes in biomedical research, contributing to the understanding of disease biology. For the past century, traditional small-molecule drugs have been the dominant model of drug research. However, new models such as proteolytic targeted chimera (PROTAC) and RNA-targeted small molecules (RSM), as well as biological approaches such as antibody-based therapies and cell and gene therapy, have been added to the drug discovery toolbox.

What role will small molecules play in future drug research? How will small molecules continue to meet patient needs in the future? In this review, we take the opportunity to review and clarify some of the historical cornerstones of small molecule drug research, discuss current and future trends in drug discovery, and present a personal vision for the future of drug research, with an emphasis on small molecule drug research.

1, From Aspirin to the Present: A Historical review of several well-known small molecule drugs

Throughout history, many small molecule drugs have contributed to medical advances and improved patients’ lives (Figure 2). Some of these early drugs are still in use today, and some have disappeared from the market, but have played an important role in improving treatment for their specific indications.

1.1 Penicillin

Penicillin is a natural antibiotic produced by fungi that has saved millions of lives (Figure 3). Scottish researcher Alexander Fleming made the discovery by chance in 1928 while returning to his laboratory after a holiday. Fleming noticed that in one of his petri dishes, an airborne fungus was blocking the growth of his staph cultures. A decade later, pure penicillin was isolated from mould fermentation and successfully applied to the first patient in 1941, before being used to treat bacterial wound infections during The Second World War. Along with Salvarsan(1910) and Prontosil(1935), the introduction of penicillin marked the beginning of the antibiotic era. After penicillin’s unique and challenging β -lactam structure was revealed by X-ray crystallography in 1945, it was not until 12 years later that it was first fully synthesized. Despite the inevitable emergence of bacterial resistance, penicillin and many structural analogues are still in use today.

1.2 Retrovir, the first anti-HIVdrug

Zidovudine  azidothymidine, AZT) is the first kind of anti-hiv drugs, is also the starting point of a medical success story, in which the deadly virus infection gradually turned into a manageable chronic disease (figure 3). Retrovir was introduced by GlaxoSmithKline in 1987 by repurposed a failed cancer drug from the 1960s. It was the first treatment for AIDS patients who first appeared in the United States in 1981. Today, combinations of small molecules from several drug classes are used in antiretroviral therapy, effectively reducing viral load to a minimum and bringing life close to normal with medication. In another sign of a difference, it is in the fight against hepatitis C virus (HCV) that small molecule antivirals have had the most recent success, with cure rates of more than 90 percent. In contrast, the first small-molecule antivirals to respond to the latest viral challenge of severe acute respiratory syndrome coronavirus type 2 (SARS-COV-2) are Veklury(remoxivir, a candidate candidate for Ebola), Pasyclovir (Nirmatrelvir + Ritonavir), A major protease (Mpro) inhibitor plus a cytochrome P450 inhibitor) and Lagevrio(Monupivir, a Venezuelan conversion drug candidate).

1.3 Rivaroxaban

Rivaroxaban is the first direct inhibitor of clotting factor Xa to be approved for additional cardiovascular indications (Figure 3). It was invented at Bayer in Wuppertal and launched in 2008 as a new anti-thrombotic drug. During the 20th century, due to changes in lifestyle and increases in life expectancy, these cardiovascular diseases have developed into the leading cause of death worldwide. By preventing unwanted blood clots from forming, anticoagulants help reduce the risk of life-threatening thromboembolic events, such as heart attack or stroke.

2, Small molecules have unique properties that enable many applications in drug discovery

2.1 Small molecules owe their success as drugs to their inherent properties, including their ability to cross biological barriers and modulate a range of different biological targets. Oral bioavailability is a key characteristic of most small molecule drugs and can be used as a standard oral administration of tablets. This convenience is a huge advantage over biological products, even though the size of the pharmacological effects may be similar. Another important feature of small molecules is their modular structure and ease of availability through chemical synthesis. This allows for rapid changes in chemical structures and systematic improvements in their performance. Finally, small molecules generally exhibit high metabolic stability and are compatible with most drug formulations and delivery pathways. The table below summarizes several of the more critical properties of small molecules.

2.2 The old drug new use

Small molecules continue to expand into new modes of action and conquer new target Spaces, expanding the classic toolbox of drug discovery. New chemical models and new ways of using small molecules have emerged, addressing biological targets that were previously considered unmedicable.

2.3 Targeted covalent inhibitors

Small molecules can bind to biological targets in non-covalent ways through intermolecular forces (such as hydrogen bonding and van der Waals forces), participate in covalent bonding to permanently modify the target, and fall in between. Early examples of covalent drugs include aspirin and penicillin. Acetylsalicylic acid covalently modifies cyclooxygenase by transferring the acetyl group to the serine residue at the active site, and penicillin covalently binds to the serine residue of penicillin binding protein through a β -lactam ring-opening mechanism. Although the covalent binding patterns of these early examples were based on chance discovery and revealed only in retrospect, targeted covalent inhibition (TCI) has recently become an increasingly relevant approach. KRAS has long been considered a difficult drug target. Covalent inhibitors are successfully addressed by binding to cysteine residues that exist only in mutant form.

2.4 Protein-protein interactions

Protein-protein interactions are essential for many cellular processes, and the stabilization and breakdown of protein-protein interactions (PPI) constitute attractive targets for therapeutic interventions. Although antibody-based PPI modulators dominate in the number of known therapeutic entities, small molecule drugs are gaining increasing attention for the reasons described above, namely their good oral bioavailability, better tissue permeability, lower immunogenicity risk, and lower development costs. Given the large binding surface area of proteins and the small size of small molecules, the design of effective small molecule PPI modulators is more challenging than small molecule enzymes or receptor binding agents. In this regard, an interesting approach is to stabilize protein binding motifs, such as a-helices, through cyclic peptide hybridization (FIG. 4).

2.5 RNA targets small molecules

While most drug targets are proteins, RNA-targeted small molecules (RTSMs) are emerging as a new therapeutic approach. For a long time, RNA was considered undoable because of a perceived lack of suitable binding sites. It is now known that RNA, although more reflexive than proteins, can exhibit discrete secondary and tertiary structures that create binding sites for small molecule interactions. It was not until 2020 that Evrysdi(Risdiplam), the first human RTSM drug, was marketed for spinal muscular atrophy (SMA)(Figure 4).

2.6 Small molecules as diagnostic agents

One non-therapeutic but clinically highly relevant application is the use of small molecules as diagnostic agents. Small molecules are widely used for imaging purposes, such as positron emission tomography (PET) tracers, X-rays, magnetic resonance imaging (MRI), ultrasound, and near-infrared contrast agents. The diversity of roles that small molecules can play reflects the diversity of applications themselves.

2.7 Use artificial intelligence to develop small molecule drugs

Digitisation and artificial intelligence (AI) are revolutionising all industries and are beginning to transform the drug discovery sector as well. Small molecules are particularly well suited to machine learning (ML) approaches. For one thing, this is because of their modular chemical structure, which can be translated into a machine-readable format. On the other hand, a large and historically growing dataset of synthetic methods, physicochemical properties, and protein-target interactions is widely available. The challenge and art is to “integrate everything” by further developing computational tools, leveraging composite data and seamlessly integrating efficient digital workflows to support pharmaceutical chemists in inventing new therapeutics for patients.

For more than 120 years, new small molecule drugs have had a positive impact not only on individual human life expectancy and quality of life, but also on society on a global scale.

The pharmaceutical industry aims to address human disease in a variety of ways, including small molecules, antibodies, nucleic acids, glycans, and cell and gene therapies. Taking into account the advantages and disadvantages in the context of a particular disease, priority is given to the patient. However, for many diseases, small molecules are often still the way of choice.

In addition to the inherent advantages of small molecules (such as flexible modes of action and adaptive drug delivery pathways), clinical efficacy can be increased through combination therapy with other drugs.Small molecules typically have a long shelf life, which allows this approach to reach more patients in need in a highly sustainable healthcare system than any other. Small molecules are ideal for addressing unmet medical needs. They are expected to continue to drive innovation in future drug research, which in turn will continue to improve patients’ lives.

reference:H. Beck et al., Drug Discovery Today (2022),

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