Computer-Aided Drug Design

Computer-Aided Drug Design

Computer-aided drug design (CADD) is a method based on computer chemistry to design and optimize lead compounds through computer simulation, calculation and budgeting of the relationship between drug and recipient biological macromolecules. The method of CADD began in the early 1980s. The combination of Computer aided molecular modeling and rational drug design has developed into a large class of methods of CADD, which is a tool for new drug research. Nowadays, with the completion of the human genome project, the rapid development of proteomics, and the discovery of a large number of genes related to human diseases, the target molecules of drugs have increased dramatically. At the same time, computer-aided drug design has made great progress in recent years, driven by computer technology.

The process of CADDFig.1 The process of CADD[1]

Principles of CADD

The structure of the binding site of the receptor macromolecule was obtained by X-single crystal diffraction technology, and molecular simulation software was used to analyze the structural properties of the binding site, such as electrostatic field, hydrophobic field, hydrogen bond site distribution and other information. Then, database searching or novel drug molecule design technology can be used to identify the molecules whose shape and physical and chemical properties match the receptor action site. After several cycles, new lead compounds can be found.

Application Classification of CADD

  1. Active Site Assay
    This method can be used to detect the atoms or groups that interact well with the active sites of biological macromolecules. The probe used for analysis can be some simple molecules or fragments, such as water or benzene ring, by analyzing the interaction between the probe and the active site, we can finally find the possible binding position of these molecules or fragments in the active site. The information about receptor binding obtained from active site analysis has implications for the design of novel drugs. At present, active site analysis software includes DRID, GREEN, HSITE, etc. In addition, some software based on Monte Carlo and simulated annealing technology, such as MCSS, HINT, BUCKETS, etc.
  2. Database Search
    There are two types of database searching methods. One is ligand-based, that is, 3D structure database search based on pharmacophore model. In this method, the pharmacophore conformation of a series of active molecules should be established first, the common pharmacophore groups should be proposed, and then the compounds that fit the pharmacophore model in the existing database should be searched. The other type of method is receptor-based, also known as molecular docking method, that is, the small molecule ligand pair to the active site of the receptor, and search for its reasonable orientation and conformation, so that the shape and interaction of the ligand and the receptor match best. In drug design, molecular docking method is mainly used to search for small molecules with good affinity to the recipient biological macromolecule from the compound database, so as to find new lead compounds. Molecular docking takes into account the binding effect of ligand and acceptor as a whole, so it can better avoid the situation of good local action and poor overall binding in other methods.
  3. New drug design
    According to the shape and properties of the active site of the receptor, the computer can automatically construct a new molecule with complementary shape and properties. This new molecule can fit well with the active site of the receptor, so it is expected to become a new lead compound. It can usually propose some new ideas and structure types, but the designed compounds need to be synthesized, sometimes even completely. The main software of the new drug design method includes LUDI, Leapfrog, GROW, SPROU, etc.

Role of CADD

In the early stages of drug research, the large number of molecules to be selected in accordance with the expected specific biological activity can be reduced to a small number; It can help medicinal chemists to make selection and comparison, and provide more active molecules to be selected for further study. To study the receptor structure of drugs, determine the pharmacodynamic structure of drugs, and provide lead compounds for drug design. At the same time, CADD also has its unique advantages: building three-dimensional chemical molecular structure model on the display screen; Using the achievements of computer chemistry over the years; On the basis of the model, the characteristics of various molecules and the interactions between molecules were calculated (the positions of atoms determined by molecular crystallization were analyzed by X-ray diffraction using chem-x molecular modeling software; To obtain the three-dimensional structure model of protein molecules); Moving molecules around the screen at will (rotating around an assumed axis, flipping and moving towards a particular bond); It can calculate molecular properties (distance and angle between two atoms, molecular volume, surface area and shape; Electronic properties of molecules, hydrogen bonds, donor/acceptor or charged group properties); Look at molecular interactions, gene binding and so on.

Now in every new drug research work of a certain scale, the research of CADD is a basic work. Every big pharmaceutical company in the world is using computer technology and is committed to developing the technology, which has a broad application prospect.


  1. Baig MH, Ahmad K, Rabbani G, Danishuddin M, Choi I. Computer Aided Drug Design and its Application to the Development of Potential Drugs for Neurodegenerative Disorders. Curr Neuropharmacol. 2018;16(6):740-748.

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