Silicon as a Bioisostere for Carbon in Drug Design

In the pursuit of novel therapeutic agents, medicinal chemists often employ the concept of bioisosterism – the replacement of one atom or group in a molecule with another atom or group having similar physical or chemical properties. Silicon, due to its chemical similarity to carbon, has emerged as a fascinating bioisostere in drug design.

Silicon in Medicinal Chemistry

Silicon, located directly below carbon in the periodic table, shares many of its chemical properties but also offers distinct advantages as a bioisostere:

  1. Larger Atomic Radius: Silicon has a larger atomic radius than carbon, which can influence molecular shape and steric interactions.
  2. Increased Lipophilicity: Compounds with silicon may exhibit increased lipophilicity compared to their carbon analogs, potentially enhancing cell membrane permeability. See this case study for an illustration of this effect.
  3. Metabolic Stability: Silicon-containing compounds often show enhanced metabolic stability, which can be beneficial in extending the drug's effective half-life in the body.

Looking at a 3D model makes these differences obvious: the Si–C bonds in silafluofen are substantially longer than C–C bonds, which alters the shape of the molecule and the dihedral preferences of other bonds.

Applications of Silicon Bioisosteres

Silicon in Drug Candidates

Silicon has been used to replace carbon in various functional groups like alcohols, ketones, and amides. These modifications have resulted in compounds with altered pharmacokinetic and pharmacodynamic profiles, sometimes leading to improved therapeutic properties.

Case Studies

Several studies have demonstrated the potential of silicon bioisosteres. For instance, replacing a carbon atom with silicon in certain compounds has resulted in increased potency, selectivity, and metabolic stability. Here's some case studies:

There are lots more papers out there: see for instance this recent review.

Challenges in Silicon Bioisosterism

Despite its potential, the use of silicon as a bioisostere presents challenges:

  1. Synthetic Difficulty: Introducing silicon into organic molecules can be more challenging than traditional carbon-based synthesis. Nevertheless, more and more Si-containing building blocks are now available: see, for instance, this list from Enamine.
  2. Predicting Biological Effects: The effects of silicon substitution on biological systems are not always predictable, necessitating extensive testing.

Computational Chemistry and Silicon Bioisosteres

Advanced computational tools are crucial in predicting the effects of silicon substitution in drug molecules. Quantum chemistry, accessible through platforms like Rowan, can provide insights into the electronic structure, reactivity, and conformational changes resulting from silicon substitution. This predictive power is invaluable in the early stages of drug design. Computational studies also aid in understanding how silicon substitution impacts a drug's metabolism, helping to predict its pharmacokinetic behavior.


The use of silicon as a bioisostere for carbon in drug design is an area of growing interest. While challenges remain, the potential for developing novel therapeutics with improved properties is significant. Continued research, aided by computational chemistry tools like those offered by Rowan, is essential for advancing our understanding and application of silicon bioisosteres in medicinal chemistry.

For researchers interested in exploring the innovative realm of silicon bioisosteres, Rowan provides the computational platform necessary for such advanced studies. Begin your journey in pioneering drug design by creating an account at