Abstract
Allosteric drugs are ligands that when bound to an allosteric site modify the conformational state of the pharmacological target, leading then to a modification of functional response upon binding of the endogenous ligand. Pharmacological targets are defined as biological entities, to which a ligand/drug binds and leads to a functional effect. Pharmacological targets can be proteins or nucleic acids. Computational approaches such as molecular dynamics (MD) sped up discovery and identification of allosteric binding sites and allosteric ligands. Classical all-atom and hybrid classical/quantum MD simulations can be generalized as simulation techniques aimed at analysis of atoms and molecular motion. Main limitations of MD simulations are related to high computational costs, that in turn limit the conformational sampling of biological systems. Indeed, other techniques have been developed to overcome limitations of MD, such as enhanced sampling MD simulations. In this chapter, classical MD and enhanced sampling MD simulations will be described, along with their application to drug discovery, with a focus on allosteric drugs.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Nussinov R, Tsai C-J (2013) Allostery in disease and in drug discovery. Cell 153:293–305. https://doi.org/10.1016/j.cell.2013.03.034
Olsen RW (2018) GABAA receptor: positive and negative allosteric modulators. Neuropharmacology 136:10–22. https://doi.org/10.1016/j.neuropharm.2018.01.036
Perszyk R, Katzman BM, Kusumoto H, Kell SA, Epplin MP, Tahirovic YA, Moore RL, Menaldino D, Burger P, Liotta DC, Traynelis SF (2018) An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups. elife 7:e34711. https://doi.org/10.7554/eLife.34711
Vallee M, Vitiello S, Bellocchio L, Hebert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarriere V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest J-M, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV (2014) Pregnenolone can protect the brain from cannabis intoxication. Science 343:94–98. https://doi.org/10.1126/science.1243985
Onuchic JN, Luthey-Schulten Z, Wolynes PG (1997) Theory of protein folding: the energy landscape perspective. Annu Rev Phys Chem 48:545–600. https://doi.org/10.1146/annurev.physchem.48.1.545
Bergonzo C, Henriksen NM, Roe DR, Swails JM, Roitberg AE, Cheatham TE 3rd (2014) Multidimensional replica exchange molecular dynamics yields a converged ensemble of an RNA tetranucleotide. J Chem Theory Comput 10:492–499. https://doi.org/10.1021/ct400862k
Marsili S, Signorini GF, Chelli R, Marchi M, Procacci P (2010) ORAC: a molecular dynamics simulation program to explore free energy surfaces in biomolecular systems at the atomistic level. J Comput Chem 31:1106–1116. https://doi.org/10.1002/jcc.21388
Platania CBM, Salomone S, Leggio GM, Drago F, Bucolo C (2012) Homology modeling of dopamine D2 and D3 receptors: molecular dynamics refinement and docking evaluation. PLoS One 7:e44316. https://doi.org/10.1371/journal.pone.0044316
Platania CBM, Di Paola L, Leggio GM, Romano GL, Drago F, Salomone S, Bucolo C (2015) Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach. Front Pharmacol 6:248. https://doi.org/10.3389/fphar.2015.00248
Corrada D, Colombo G (2013) Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations. J Chem Inf Model 53:2937–2950. https://doi.org/10.1021/ci400416e
Platania CBM, Giurdanella G, Di Paola L, Leggio GM, Drago F, Salomone S, Bucolo C (2017) P2X7 receptor antagonism: implications in diabetic retinopathy. Biochem Pharmacol 138:130–139. https://doi.org/10.1016/j.bcp.2017.05.001
De Ruvo M, Giuliani A, Paci P, Santoni D, Di Paola L (2012) Shedding light on protein-ligand binding by graph theory: the topological nature of allostery. Biophys Chem 165–166:21–29. https://doi.org/10.1016/j.bpc.2012.03.001
Di Paola L, Giuliani A (2015) Protein contact network topology: a natural language for allostery. Curr Opin Struct Biol 31:43–48. https://doi.org/10.1016/j.sbi.2015.03.001
Di Paola L, Platania CBM, Oliva G, Setola R, Pascucci F, Giuliani A (2015) Characterization of protein-protein interfaces through a protein contact network approach. Front Bioeng Biotechnol 3:170. https://doi.org/10.3389/fbioe.2015.00170
Newman MEJ (2006) Modularity and community structure in networks. Proc Natl Acad Sci U S A 103:8577–8582. https://doi.org/10.1073/pnas.0601602103
Hu G, Di Paola L, Liang Z, Giuliani A (2017) Comparative study of elastic network model and protein contact network for protein complexes: the hemoglobin case. Biomed Res Int 2017:2483264. https://doi.org/10.1155/2017/2483264
Doruker P, Atilgan AR, Bahar I (2000) Dynamics of proteins predicted by molecular dynamics simulations and analytical approaches: application to alpha-amylase inhibitor. Proteins 40:512–524
Bernardi RC, Melo MCR, Schulten K (2015) Enhanced sampling techniques in molecular dynamics simulations of biological systems. Biochim Biophys Acta 1850:872–877. https://doi.org/10.1016/j.bbagen.2014.10.019
Lu S, Ji M, Ni D, Zhang J (2018) Discovery of hidden allosteric sites as novel targets for allosteric drug design. Drug Discov Today 23:359–365. https://doi.org/10.1016/j.drudis.2017.10.001
Dror RO, Pan AC, Arlow DH, Borhani DW, Maragakis P, Shan Y, Xu H, Shaw DE (2011) Pathway and mechanism of drug binding to G-protein-coupled receptors. Proc Natl Acad Sci U S A 108:13118–13123. https://doi.org/10.1073/pnas.1104614108
Yang C-Y (2015) Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method. PLoS One 10:e0118671. https://doi.org/10.1371/journal.pone.0118671
Wang J, Wang Y, Cui W-W, Huang Y, Yang Y, Liu Y, Zhao W-S, Cheng X-Y, Sun W-S, Cao P, Zhu MX, Wang R, Hattori M, Yu Y (2018) Druggable negative allosteric site of P2X3 receptors. Proc Natl Acad Sci U S A 115:4939–4944. https://doi.org/10.1073/pnas.1800907115
Das A, Gur M, Cheng MH, Jo S, Bahar I, Roux B (2014) Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. PLoS Comput Biol 10:e1003521. https://doi.org/10.1371/journal.pcbi.1003521
Karasawa A, Kawate T (2016) Structural basis for subtype-specific inhibition of the P2X7 receptor. elife 5:e22153. https://doi.org/10.7554/eLife.22153
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Platania, C.B.M., Bucolo, C. (2021). Molecular Dynamics Simulation Techniques as Tools in Drug Discovery and Pharmacology: A Focus on Allosteric Drugs. In: Di Paola, L., Giuliani, A. (eds) Allostery. Methods in Molecular Biology, vol 2253. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1154-8_14
Download citation
DOI: https://doi.org/10.1007/978-1-0716-1154-8_14
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-1153-1
Online ISBN: 978-1-0716-1154-8
eBook Packages: Springer Protocols