- April 6, 2023
Small molecule drug discovery has led to numerous medical breakthroughs that have transformed the treatment of various diseases such as Cancer, viral infections, Neurodegenerative diseases, etc. In the future, with the continuous advancement of science and technology, the development of small-molecule drug discovery continues to hold great promise for the development of new treatments and the promotion of medical breakthroughs.
Drug discovery is a complex and challenging task, from “target identification” to “lead identification” when compounds show activity against biological targets, from “target identification” when pharmacokinetics (ADME) and potency are optimized Lead Optimization,” and finally to “Candidate Drug Selection” when selecting clinical candidates for safety studies. The entire process can be time-consuming and resource-intensive and is highly dependent on translational methods that involve assumptions that may not be testable due to a lack of human data and, thus, may not be accurate for the drug under study. These may result in substantial capital losses and higher drug development costs.
Small molecules continue to drive medical breakthroughs and address unmet medical needs, saving countless lives. Furthermore, small molecules are crucial in biomedical research as chemical probes that contribute to understanding disease biology. In the past century, traditional small-molecule drugs have been the dominant way of drug research, as shown in the figure below:
Small molecules continue to expand into new modes of action and achieve recent achievements, extending the classic toolbox of drug discovery:
Small Molecule Drugs : Antibody-Drug Conjugates
Small molecule drug conjugates consist of a small molecule covalently linked to a second molecule with a unique biological function. This concept of bifunctional molecules has matured considerably over the past few decades. The task of the second molecule is to target the conjugate to the intended site of action so that the first molecule can exert its pharmacological activity with high specificity.
Antibody-drug conjugates (ADCs) are a prominent example, which use highly selective antibodies to direct the conjugate to the target site. Following internalization of the ADC and cleavage of the small molecule from the antibody cell, high local concentrations of the pharmacologically active small molecule are generated in a microenvironment-specific manner. Local concentrations increase, systemic drug concentrations in the body are reduced, and overall side effects are reduced.
Small Molecule Drugs : RNA targeting small molecules
While most drug targets are proteins, RNA-targeting small molecules (RTSMs) are emerging. Human RNA has long been considered undruggable because it was thought to need more suitable binding sites. It is now known that RNA can assume discrete secondary and tertiary structures that provide binding sites for small molecules to interact with.
It was not until 2020 that the first human RTSM drug, Evrysdi (risdiplam), was approved for the treatment of spinal muscular atrophy (SMA) (Figure 4). SMA is a genetic disorder that reduces levels of the Survival Motor Neuron (SMN) protein LeadLead to severe muscle weakness.
Risdiplam acts as a splicing modifier on SMN2 mRNA, incorporating the exon into transcription, increasing functional SMN protein. So risdiplam is about to change how the disease works, and its approval has attracted much attention. In addition to targeting mRNAs encoding disease-associated proteins such as risdiplam, non-coding mRNAs offer a potentially more significant target space whose regulatory functions and disease-driving potential we are only beginning to understand.
Small Molecule Drugs : PROTAC
PROTACs are protein-degrading bifunctional drug conjugates that consist of two covalently linked small molecule moieties: one binds the target protein, and the other binds the E3 ligase. E3 ligases transfer ubiquitin to their native protein substrates, facilitating proteasomal degradation. PROTACs can “hijack” this mechanism by bringing the target protein close to the ligase, which transfers the ubiquitin to the target protein even if it is not a natural substrate for the ligase.
During the lead optimization phase of discovery, molecules are evaluated using various in vitro assays to characterize potency, physicochemical properties, and ADME properties. Preclinical in vivo studies were subsequently performed to characterize the pharmacokinetics (PK) and pharmacodynamics (PD).
PK is the study that studies pharmacokinetics which depends heavily on ADME processes in the body. In contrast, PD quantifies the effect of a drug on the body. It can include multiple kinetics such as biomarker response, tumor progression, cytokine release, etc. 3 Several physicochemical properties of a drug affect its PK behavior, including molecular weight, lipophilicity, and permeability. Furthermore, the body’s physiology can challenge the exposure to a drug and, thus, its efficacy.
Technological improvements in instrumentation and quantitative methods have enabled the screening of large molecules for potency and ADME properties, thereby classifying large numbers of molecules to identify high-quality drug candidates. This leads to generating large datasets that can be used for machine learning (ML) to predict various properties based on molecular structure. These large datasets can be incorporated into ML models to reduce the risk profile of NME without experimentation.
Using in silico ML models increases the number of compounds screened and reduces screening time. This paradigm enables researchers to move from a “trial and error” approach that relies solely on expert intuition to more efficient and automated screening and selection strategies. Although several efforts have been documented in the early stages of the drug discovery pipeline, such as target identification and hit discovery, the potential to apply these techniques to later stages of the process could be more precise.
ML can significantly reduce the experimental burden and timetable currently used for in vitro and in vivo drug response characterization. To this end, a growing body of work is attempting to characterize and capture the implicit relationships between molecular structures, properties, and PK behavior.
Medicilon used automated blood collection technology more than ten years ago. Currently, Medicilon has a variety of new high-content screening technologies and methods and has established an advanced drug target screening technology platform, which can collect blood quickly. All aspects of drug target information to solve the bottleneck of drug target development are “long time-consuming, low accuracy, poor repeatability.” Medicilon provides customers with new drug development services covering various targets and disease areas, including active compound discovery, drug target screening, validation, and Lead compound optimization to preclinical candidate drug selection.
Summarize
Today, the pharmaceutical industry aims to address human disease in various ways, including small molecules, antibodies, nucleic acids, glycans, and cell and gene therapies. Mode-specific decisions are prioritized in a patient-centered manner, considering the benefits and harms in the specific disease context. However, small molecules are often the modality of choice for many diseases.
Small molecules have played an essential role as milestone drugs in the history of medicine and have influenced medical progress and social change. For medicinal chemists, small molecules have always been the perfect way to optimize drug potency and selectivity and fine-tune overall molecular properties. Given the modular nature of small molecules and the virtually limitless possibilities for combinations to generate bioactive molecules, there are no limits to new applications, including previously undruggable target space issues, which may no longer be a hindrance. Small-molecule drugs are well-suited to address unmet medical needs. They are expected to continue driving innovation in future drug research, thereby improving patients’ quality of life.
References:
[1] Hartmut Beck, Michael Härter, et al. Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research Laboratory. Drug Discov Today. 2022 Jun;27(6):1560-1574. doi: 10.1016/j.drudis.2022.02.015.
[2] Nikhil Pillai, Aparajita Dasgupta, et al. Machine Learning guided early drug discovery of small molecules. Drug Discov Today. 2022 Aug;27(8):2209-2215. doi: 10.1016/j.drudis.2022.03.017.
[3] Tong, Juliana TW, et al. “An insight into FDA approved antibody-drug conjugates for cancer therapy.” Molecules 26.19 (2021): 5847. https://doi.org/10.3390/molecules26195847
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