Computational combinatorial ligand design: application to human alpha-thrombin

Journal of Computer-aided Molecular Design
A Caflisch

Abstract

A new method is presented for computer-aided ligand design by combinatorial selection of fragments that bind favorably to a macromolecular target of known three-dimensional structure. Firstly, the multiple-copy simultaneous-search procedure (MCSS) is used to exhaustively search for optimal positions and orientations of functional groups on the surface of the macromolecule (enzyme or receptor fragment). The MCSS minima are then sorted according to an approximated binding free energy, whose solvation component is expressed as a sum of separate electrostatic and nonpolar contributions. The electrostatic solvation energy is calculated by the numerical solution of the linearized Poisson-Boltzmann equation, while the nonpolar contribution to the binding free energy is assumed to be proportional to the loss in solvent-accessible surface area. The program developed for computational combinatorial ligand design (CCLD) allows the fast and automatic generation of a multitude of highly diverse compounds, by connecting in a combinatorial fashion the functional groups in their minimized positions. The fragments are linked as two atoms may be either fused, or connected by a covalent bond or a small linker unit. To avoid the combinatorial expl...Continue Reading

References

Jan 1, 1979·Thrombosis Research·C Kettner, E Shaw
Oct 1, 1991·Journal of Medicinal Chemistry·S W Fesik
Sep 20, 1991·Journal of Molecular Biology·T J RydelR Huber
Oct 18, 1990·Nature·M Karplus, G A Petsko
Feb 14, 1971·Journal of Molecular Biology·B Lee, F M Richards
Jun 5, 1982·Journal of Molecular Biology·J Warwicker, H C Watson
Jun 1, 1995·Journal of Computer-aided Molecular Design·P R Gerber, K Müller
May 26, 1995·Science·B Honig, A Nicholls
Feb 10, 1995·Journal of Molecular Biology·L TaberneroJ S Sack
Nov 11, 1994·Journal of Medicinal Chemistry·K HilpertT B Tschopp
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Oct 1, 1993·Trends in Pharmacological Sciences·C TapparelliN S Cook
Sep 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·B E MaryanoffA Liu
Jun 11, 1993·Journal of Medicinal Chemistry·S H Rotstein, M A Murcko
Feb 1, 1996·Journal of Computer-aided Molecular Design·P D Grootenhuis, M Karplus

❮ Previous
Next ❯

Citations

Jul 28, 2007·Journal of Computer-aided Molecular Design·Erik EvensenMartin Karplus
Jun 10, 2009·Journal of Computer-aided Molecular Design·Christian R Schubert, Collin M Stultz
Dec 22, 1999·Pharmacology & Therapeutics·D Joseph-McCarthy
Jul 14, 2001·Journal of Molecular Graphics & Modelling·S AhmedA Caflisch
Aug 1, 1997·Current Opinion in Chemical Biology·R S Bohacek, C McMartin
Jul 17, 1998·Current Opinion in Chemical Biology·M L Lamb, W L Jorgensen
Feb 3, 2009·Journal of Cellular and Molecular Medicine·Vincent ZoeteOlivier Michielin
Feb 27, 2014·Bioorganic & Medicinal Chemistry Letters·Hongtao Zhao, Amedeo Caflisch
Apr 1, 2015·Future Medicinal Chemistry·David R Hall, Istvan J Enyedy
May 3, 2011·Journal of Chemical Information and Modeling·Muhammad K HaiderRoderick E Hubbard
Mar 17, 1999·Journal of Molecular Recognition : JMR·H A Chase
Apr 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Martina L JonesJun Zeng
Nov 3, 2004·Nature Reviews. Drug Discovery·Douglas B KitchenJürgen Bajorath
Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lucas A DefelipeXavier Barril
Jun 8, 2001·News in Physiological Sciences : an International Journal of Physiology Produced Jointly by the International Union of Physiological Sciences and the American Physiological Society·Amedeo CaflischClaus Ehrhardt
Mar 1, 2008·Journal of Chemical Information and Modeling·Fabian Dey, Amedeo Caflisch
Aug 20, 2004·Journal of Medicinal Chemistry·Martina SchechnerAnnick P Dejaegere
Dec 26, 2001·Journal of the American Chemical Society·D Joseph-McCarthyM Karplus
Sep 13, 2002·Journal of the American Chemical Society·Finton SirockinAnnick Dejaegere

❮ 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.