Methyl Effects on Protein-ligand Binding

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Apr 17

PMID 22500930

Citations 89

Authors

Cheryl S Leung

Siegfried S F Leung

Julian Tirado-Rives

William L Jorgensen

Affiliations

Soon will be listed here.

Abstract

The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.

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References

Erion M, Dang Q, Rami Reddy M, Kasibhatla S, Huang J, Lipscomb W . Structure-guided design of AMP mimics that inhibit fructose-1,6-bisphosphatase with high affinity and specificity. J Am Chem Soc. 2007; 129(50):15480-90. DOI: 10.1021/ja074869u. View

Andrews P, Craik D, Martin J . Functional group contributions to drug-receptor interactions. J Med Chem. 1984; 27(12):1648-57. DOI: 10.1021/jm00378a021. View

Bollini M, Domaoal R, Thakur V, Gallardo-Macias R, Spasov K, Anderson K . Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents. J Med Chem. 2011; 54(24):8582-91. PMC: 3258498. DOI: 10.1021/jm201134m. View

Abel R, Young T, Farid R, Berne B, Friesner R . Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J Am Chem Soc. 2008; 130(9):2817-31. PMC: 2761766. DOI: 10.1021/ja0771033. View

Jorgensen W, Tirado-Rives J . Molecular modeling of organic and biomolecular systems using BOSS and MCPRO. J Comput Chem. 2005; 26(16):1689-700. DOI: 10.1002/jcc.20297. View

Michel J, Tirado-Rives J, Jorgensen W . Prediction of the water content in protein binding sites. J Phys Chem B. 2009; 113(40):13337-46. PMC: 2891159. DOI: 10.1021/jp9047456. View

Jorgensen W . Efficient drug lead discovery and optimization. Acc Chem Res. 2009; 42(6):724-33. PMC: 2727934. DOI: 10.1021/ar800236t. View

Michel J, Verdonk M, Essex J . Protein-Ligand Complexes: Computation of the Relative Free Energy of Different Scaffolds and Binding Modes. J Chem Theory Comput. 2015; 3(5):1645-55. DOI: 10.1021/ct700081t. View

Tirado-Rives J, Jorgensen W . Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding. J Med Chem. 2006; 49(20):5880-4. DOI: 10.1021/jm060763i. View

10.

Chodera J, Mobley D, Shirts M, Dixon R, Branson K, Pande V . Alchemical free energy methods for drug discovery: progress and challenges. Curr Opin Struct Biol. 2011; 21(2):150-60. PMC: 3085996. DOI: 10.1016/j.sbi.2011.01.011. View

11.

Brameld K, Kuhn B, Reuter D, Stahl M . Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis. J Chem Inf Model. 2008; 48(1):1-24. DOI: 10.1021/ci7002494. View

12.

Bissantz C, Kuhn B, Stahl M . A medicinal chemist's guide to molecular interactions. J Med Chem. 2010; 53(14):5061-84. PMC: 2905122. DOI: 10.1021/jm100112j. View

13.

Senger S, Chan C, Convery M, Hubbard J, Shah G, Watson N . Sulfonamide-related conformational effects and their importance in structure-based design. Bioorg Med Chem Lett. 2007; 17(10):2931-4. DOI: 10.1016/j.bmcl.2007.02.034. View

14.

Liu K, Huang X, Bagrodia S, Chen J, Greasley S, Cheng H . Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011; 21(4):1270-4. DOI: 10.1016/j.bmcl.2010.12.026. View

15.

Jorgensen W, Tirado-Rives J . Potential energy functions for atomic-level simulations of water and organic and biomolecular systems. Proc Natl Acad Sci U S A. 2005; 102(19):6665-70. PMC: 1100738. DOI: 10.1073/pnas.0408037102. View

16.

Barreiro E, Kummerle A, Fraga C . The methylation effect in medicinal chemistry. Chem Rev. 2011; 111(9):5215-46. DOI: 10.1021/cr200060g. View

17.

Lu N, Kofke D, Woolf T . Improving the efficiency and reliability of free energy perturbation calculations using overlap sampling methods. J Comput Chem. 2003; 25(1):28-39. DOI: 10.1002/jcc.10369. View

18.

Lamb M, Jorgensen W . Computational approaches to molecular recognition. Curr Opin Chem Biol. 1998; 1(4):449-57. DOI: 10.1016/s1367-5931(97)80038-5. View

19.

Steinbrecher T, Hrenn A, Dormann K, Merfort I, Labahn A . Bornyl (3,4,5-trihydroxy)-cinnamate--an optimized human neutrophil elastase inhibitor designed by free energy calculations. Bioorg Med Chem. 2007; 16(5):2385-90. DOI: 10.1016/j.bmc.2007.11.070. View

20.

Kopecky D, Hao X, Chen Y, Fu J, Jiao X, Jaen J . Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors. Bioorg Med Chem Lett. 2008; 18(24):6352-6. DOI: 10.1016/j.bmcl.2008.10.092. View