Drug design

Active ingredient design (also called rational active ingredient design ) refers to the targeted design of active ingredients . These active ingredients are used, among other things, in the development of pharmaceuticals or pesticides . The targeted design of active ingredients is based on finding and optimizing lead structures that bind to a target as part of a ligand . Drug design is a form of rational design .

properties

Most of the time, an active ingredient is a small molecule , a recombinant protein or a vector that has an effect on living things . This effect mostly takes place through the binding of the active substance to a protein , whereby its effect can be strengthened or weakened. The active ingredients are often complementary in shape and charge to the binding site on the protein. (The whole thing is described with the key-lock principle .) Active ingredients with a similar shape and charge ( structural analogues ) usually have similar effects. The drug design is often supported by molecular modeling such as PK / PD modeling . In contrast to the classic high-throughput screening of molecule libraries, drug design uses knowledge about the molecular structures of the ligand and target . For an active ingredient design, the activation or inhibition of a target must correlate with an effect and the form of the target must also enable the binding of a ligand ( druggability , active ingredient binding ability ). In a narrower sense, drug design refers to the design of ligands for a target that only produces an effect when the pharmacophore binds . The active ingredient design includes the adaptation of properties of the active ingredient such as pharmacodynamics , effective dose , (ideally oral) bioavailability , plasma half-life , metabolism , protective quotient , toxicity and adverse drug effects . Various methods exist for this, such as the Rule of Five , lipophilic efficiency or SPORCalc .

Types

Schematic sequence of two strategies, ligand-based and structure-based drug design

The drug design has two different approaches, some of which can be combined, the ligand-based and the structure-based drug design.

Ligand-based

Ligand-based drug design (also known as indirect drug design ) uses drugs that are similar in shape and charge, for which an effect is empirically known. The active ingredients are identified through high throughput screening . From their molecular structure, conclusions can be drawn about the shape of the binding site on the target and a quantitative structure-activity relationship can be determined. This enables a limited prediction of the binding of other substances to this point.

Structure-based

The structure-based active ingredient design (also direct active ingredient design ) is based on the knowledge of the molecular structure and that of the target ( protein structure ), which was obtained by crystal structure analysis or nuclear magnetic resonance spectroscopy .

Within the structure-based approach, an active ingredient can be identified via a database search (if available) or, based on knowledge of the structure of the target, can be constructed and then synthesized. This reduces the average number of trials. In scaffold hopping , the non-binding structure of the pharmacophore is varied.

Determination of the binding site

The binding site for the pharmacophore is identified by protein characterization, e.g. B. an active center of an enzyme . The atoms participating in the bond are examined, for which purpose the structure of the target is usually determined when the ligand is bound. The typical interactions are mediated by typical atoms:

• hydrophobic atoms in aliphatic and aromatic amino acids
• Donor of a hydrogen bond through an oxygen or nitrogen atom with hydrogen
• Acceptor of a hydrogen bond through an oxygen or nitrogen atom with a free electron pair
• Polar atoms with no hydrogen participation such as oxygen, nitrogen, sulfur, phosphorus, chlorine, iodine, metal ions and polarized carbon atoms (connected to preceding heteroatoms).

Ligand fragments

Flow chart of the structure-based drug design

The structure of the ligand can also be divided into the shapes of its components (shape motifs) in the course of modeling, which are also referred to as fragments . By successively adding to the first fragment (English seed 'seedling'), the size of the ligand designed in this way increases. Although there are only a few fragments, many different molecules can be created by combining them. To determine the potential energy surface, mainframes are used to calculate the free energy of the respective bond in order to identify the lowest potential energy between the bond surface and the pharmacophore. To save computer time and capacity, the steps are prioritized, e.g. B. tightly binding fragments are preferred in the calculation. After determining the binding fragments for several binding sites, these are combined to form one molecule. The lowest potential energy conformation enables higher affinity binding of the ligand.

Valuation methods

The structure-based active ingredient design calculates the optimal ligands, especially with regard to a binding as affine as possible to the target . One evaluation method considers the free enthalpy associated with the attachment :

${\displaystyle {\begin{array}{lll}\Delta G_{\text{Bindung}}=-RT\ln K_{\text{d}}\\[1.3ex]K_{\text{d}}={\dfrac {[{\text{Target}}][{\text{Ligand}}]}{[{\text{Komplex}}]}}\\[1.3ex]\Delta G_{\text{Bindung}}=\Delta G_{\text{Desolvatation}}+\Delta G_{\text{Molekularbewegung}}+\Delta G_{\text{Konfiguration}}+\Delta G_{\text{Interaktion}}\end{array}}}$

the free enthalpy is composed of four elements: ${\displaystyle \Delta G_{\text{Bindung}}}$

• Desolvation - enthalpy of removal of the ligand from the solvent
• Molecular motion - decrease in entropy by reducing the degrees of freedom in binding
• Configuration - necessary conformational changes for binding
• Interaction - enthalpy gain through the interactions at the contact surface

Different calculation methods can be used for each of the free enthalpies or energies.

Web links

• MeSH active ingredient design

Individual evidence

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3. ^ Cohen, N. Claude: Guidebook on Molecular Modeling in Drug Design . Academic Press, Boston 1996, ISBN 0-12-178245-X .
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