Predicting binding modes from free energy calculations

Journal of Medicinal Chemistry
M NervallJohan Aqvist

Abstract

To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal structure that resulted in two distinct clusters of possible conformations. One of these clusters was compatible with an existing crystal structure, whereas the other displayed a flipped heterocyclic group. Binding free energies, using the non-native crystal structure, calculated from several scoring functions, were similar for the two clusters, and no conclusion about the binding mode could be drawn from these results. The two clusters could be separated through rescoring with the linear interaction method (LIE) in combination with molecular dynamics simulations, which leads to a binding mode prediction in line with experimental crystallographic data. Further, the LIE model produces the best correlation between experimental and calculated binding free energies among the tested scoring methods.

References

Mar 1, 1994·Protein Engineering·J AqvistJ E Samuelsson
Apr 4, 1997·Journal of Molecular Biology·G JonesR Taylor
May 7, 1998·Journal of Computer-aided Molecular Design·T HanssonJ Aqvist
Apr 12, 2001·Current Opinion in Structural Biology·H Gohlke, G Klebe
Jul 18, 2001·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·J MareliusJ Aqvist
Aug 29, 2002·Journal of Computer-aided Molecular Design·Renxiao WangShaomeng Wang
Oct 5, 2002·Journal of Computer-aided Molecular Design·R D TaylorJ W Essex
Aug 7, 2003·Bioorganic & Medicinal Chemistry·Karolina ErsmarkAnders Hallberg
Aug 12, 2003·Proteins·Marcel L VerdonkRichard D Taylor
Mar 20, 2004·Science·William L Jorgensen
Nov 13, 2004·Journal of Medicinal Chemistry·Andrew L HopkinsDavid K Stammers
Nov 13, 2004·Journal of Medicinal Chemistry·George A FreemanJoseph H Chan
Jan 24, 2006·Journal of Chemical Information and Modeling·J Christian BaberMiklos Feher
Jan 24, 2006·Journal of Chemical Information and Modeling·Akifumi OdaShuichi Hirono
Aug 31, 2006·Biochemistry·Hugo Gutiérrez-de-TeránJohan Aqvist
Sep 29, 2006·Journal of Medicinal Chemistry·Gregory L WarrenMartha S Head

❮ Previous
Next ❯

Citations

Jul 26, 2011·Journal of Chemical Information and Modeling·Chaya RappMatthew P Jacobson
Sep 26, 2013·Journal of Chemical Information and Modeling·Vedat DurmazMarcus Weber
Jun 26, 2009·BMC Bioinformatics·Helena Strömbergsson, Gerard J Kleywegt
Oct 29, 2013·BMC Structural Biology·Sandipan ChakrabortyPradip K Biswas
Mar 24, 2011·Future Medicinal Chemistry·Predrag Kukić, Jens Erik Nielsen
Oct 22, 2015·Journal of Biomolecular Structure & Dynamics·Yeng-Tseng Wang, Tian-Lu Cheng
Dec 23, 2008·Biochemical and Biophysical Research Communications·Hajime SugiyamaYutaka Tamura
Jun 2, 2010·Biophysical Journal·Eva Stjernschantz, Chris Oostenbrink
Sep 23, 2009·Journal of Chemical Information and Modeling·Yeng-Tseng WangCheng-Lung Chen
Apr 7, 2012·The Journal of Physical Chemistry. B·M Harunur Rashid, Serdar Kuyucak
May 3, 2014·Journal of Chemical Information and Modeling·Yasmin Shamsudin KhanJohan Åqvist
Mar 10, 2011·Journal of Chemical Information and Modeling·Lucía DíazJohan Åqvist

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.