I believe that pharmaceutical industries rarely using quantum mechanics (QM) in drug design research, due to the relative fast pace of their work. Academic researchers do employ QM in such research, but I can’t think of an example of where this has directly lead to a new and patented drug entity. Often QM theories are used to understand the quantum nature of an active compound (e.g. reactions involving radicals or bond formation/breaking). Another way that QM is used is to develop and optimize faster methodologies that are more frequently used in this type of research, such as force-field parameterization of bonded and nonbonded (e.g. partial atomic charges, Lennard-Jones parameters) terms for molecular mechanics, molecular dynamics, and docking calculations. Such use of QM is not only in creating a computational model of the drug, but also in creating models of biological entities (e.g. proteins, carbohydrates, DNA) and for solvent molecules that are involved in drug transportation, binding, signaling, and et cetera.
In my personal work I have several examples of using QM in the two manners I stated above. If you are interested, then take a quick look at the following representative papers. Perhaps they will get you started on finding additional work done by other researchers (i.e. references therein and citations thereof).
Personal work:
1. Efficient and accurate characterization of the Bergman cyclization for several enediynes including an expanded substructure of esperamicin A1.
2. Ortho effect in the Bergman cyclization: electronic and steric effects in hydrogen abstraction by 1-substituted naphthalene 5,8-diradicals.
3. GLYCAM06: a generalizable biomolecular force field. Carbohydrates.
4. A Glycam-Based Force Field for Simulations of Lipopolysaccharide Membranes: Parametrization and Validation
5. Thiopeptide Antibiotics and the Ribosomal 23S-L11 Subunit -- a Challenging Use Case for Semi-Automatic Force-Field Development
Here are a few more external articles that directly addresses the topic:
1. Rational drug design. (http://www.ncbi.nlm.nih.gov/pubmed/19835861)
2. Partial atomic charges and their impact on the free energy of solvation. (http://www.ncbi.nlm.nih.gov/pubmed/22996256)
3. A perspective on quantum mechanics calculations in ADMET predictions. (http://www.ncbi.nlm.nih.gov/pubmed/23675934)
4. The future of prodrugs - design by quantum mechanics methods. (http://www.ncbi.nlm.nih.gov/pubmed/23540707)
5. The application of quantum mechanics in structure-based drug design. (http://informahealthcare.com/doi/abs/10.1517/17460441.2013.752812)
Kind regards,
Karl
Thank you very much Karl Kirschner,
What is your opinion regarding molecular surface study using Quantum mechanics of various structurally different lead molecule. What is a success rate using this methodology?
I am not aware of any study that only uses molecular surface for drug design. There are different ways to compute a molecular surface, and each of them will effect the resulting topology. What I am aware is its use to investigate how well, or complementary, a ligand sits within a binding pocket. However, typical comparison between molecular structures are often done with simple ball-and-stick representations. You many also want to look into computing similarity metrices (e.g. Tanimoto-Coefficients) of compounds, and the research issues that go into these calculations. Perhaps there are some articles out there that will better address you questions.
Kind regards,
Karl
Maybe this reference can be helpful.
Lodola A, De Vivo M.
The increasing role of QM/MM in drug discovery.
Adv Protein Chem Struct Biol. 2012;87:337-62. doi: 10.1016/B978-0-12-398312-1.00011-1.
Well, we use QM methods a lot. COSMO-RS, COSMOtherm, COSMOsim, COSMOsim-3D, COSMOsar-3D are all useful approaches to compound properties emerging from their interaction surfaces. Please have a look at www.cosmologic.de
for more detailed information, articles, and in depth theoretical background.
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