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Small Molecule Drug Candidates

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Modern drug development is no longer a “Shen Nong tastes herbs” model. First, it is ethically not allowed. Drugs that enter the clinic must not only have a certain basis for patient benefit, but also ensure safety. Second, if certain screening is not carried out, there are too many compounds to be tested clinically, which will bring great difficulties to recruiting patients. Third, if clinical drugs are not screened, the failure rate will be very high, and manufacturers cannot afford it from an economic point of view.
There are several concepts that need to be clarified: the drugs entering the clinic are called candidate drugs; the research process of finding candidate drugs is called drug discovery; and the clinical research of selecting drugs to market, determining the indications, and applying the population is called drug development.
The appearance of drug molecules is not so different from the hundreds of millions of known molecules, and it is a drop in the ocean among astronomical virtual molecules. If you compare any single biological property, the drug molecule is not necessarily the best in the same series.
The core feature of drug properties is balance, that is, all properties meet a certain standard. This feature makes the discovery of new drugs difficult. Because drug molecules are close to other molecules, it is almost impossible to find drugs based on their molecular structure. Because properties are required to be balanced, each candidate molecule must be tested for all properties in order to know which one can become a drug, so the drug discovery process is tedious and complicated.

High-throughput screening

It is obviously unrealistic to test every property of every known compound, so there is a screening pipeline for drug discovery. The most upstream of the pipeline is the cheapest and most screening throughput testing method, and the downstream is the complex and expensive testing method. The current R&D model starts with regulating the biological activity of the target protein, usually through high-throughput screening of a large number of compounds (HTS).
This is only the most upstream in form. In fact, the design of the compound library has excluded a large number of so-called non-drug compounds, such as predictive drugs that contain toxic groups such as thiourea, metabolically unstable groups such as ester groups, and violate the “5 rules”. Compounds with regular generation properties are generally not in the compound library. These principles are also applicable in the later optimization stage. Compound libraries are generally derivatives of known active molecular skeletons or similar structures, so those that can enter the compound library have gone through several rounds of elimination.

Find the hit/lead compounds

It is difficult for HTS to find compounds with good enough properties, but it is usually possible to find so-called hits that can be optimized to the drug molecule level, and leads that have been verified for activity and are optimizable.
These compounds require complex optimization processes to select drug molecules. Depending on the physiological and pathological function of a specific target, the binding strength of endogenous ligands and other factors, different targets are targeted, and the ligands require different activities.
The current optimization technology can generally increase the activity of the lead compound by 100 to 1000 times, so if the drug activity is required to be 1nM, the lead activity should be about 1uM. If the crystal structure of the target is known, the optimization efficiency can sometimes be greatly improved, so analyzing the crystal structure of the target protein is an important work in the early stage of the project.

Balance optimization of other properties

While improving the activity, it is necessary to balance the optimization of many other properties. The selectivity, metabolic stability and other pharmacokinetic properties and activities of compounds must be optimized simultaneously. Some common undesirable biological properties need to be removed later, such as inhibition and induction of the detoxification enzyme CYP, hERG activity that interferes with myocardial electrophysiology, and genotoxicity. Different diseases have different requirements for the properties of compounds. For example, cancer drugs usually tolerate more design flaws than weight-loss drugs.
When the properties are close to the drug level, these optimized compounds have to be tested in more complex and expensive short-term and long-term animal efficacy (usually multiple doses, multiple species), cell and overall animal level safety, toxicity and other experiments. In addition, the problem of large-scale synthesis (kilogram level) of drug molecules must also be resolved.

Increased importance of mechanism

An important feature of modern drug candidates is that the efficacy of animal experiments comes from the target. Although the targets of many successful drugs are unknown, the current discovery process of new drugs and the stringent requirements of drug regulatory authorities on drug performance make the mechanism more important than before. The importance of the mechanism is mainly that for the developer, the patient does not care about the mechanism through which the drug takes effect.
If the mechanism and its related biomarkers are very beneficial to the selection of patients, the prevention of side effects, and the interpretation of non-responders, the development risk can be greatly reduced. Therefore, the candidate drug must not only have a dose-dependent animal activity, but also the free drug concentration of the target tissue must be sufficient to inhibit the target protein, and there must be relevant evidence, usually the so-called biomarker downstream of the protein changes in the therapeutic dose.

Don’t do anything that shouldn’t be done

Finally, for drug candidates, not only must the things that should be done be done well, but also the things that should not be done must not be done.
This compound and the target protein generally have a binding strength of less than 10nM, and the binding strength of all other proteins is greater than 100nM, and the binding strength of hERG, CYP and other toxic consequence proteins is lower. The compound must be able to be made into a dosage form required for clinical use, be stable enough in the body, reasonably distributed, and have sufficient free drug concentration in the target tissue. The compound must show dose-dependent efficacy, efficacy intensity and compound activity in animal models, and the function of the target is related to changes in mechanism biomarkers. Generally, there will be no safety and toxicity issues at more than 10-30 times the dose. This compound must also be able to be produced in large quantities at a relatively low cost.
Not every project can find such a compound. The main obstacle is the parallelism between activity/target tissue concentration, biomarkers, and efficacy. For example, if a compound has curative effect in an animal model, but an inactive or active analogue with a very low target tissue concentration also has curative effect, the observed effect may be false positive.

Conclusion <<<
Even for such a highly optimized compound, the success rate of entering the clinic is still very low, mainly because the current level of technology cannot accurately define what kind of drug candidate can achieve 100% success in the clinic. Although the criteria mentioned above are very complicated, they are still far from predicting clinical manifestations. Now, on average, 30 of every 60 drug candidates can enter clinical studies through GLP toxicity tests, 3 can finally be marketed, and 1 of them can become a star drug for the company’s survival.

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