Molecular Dynamics Protocols for the Study of Cyclodextrin Drug Delivery Systems.

Hypertension treatment is a current therapeutic priority as there is a constantly increasing part of the population that suffers from this risk factor, which may lead to cardiovascular and encephalic episodes and eventually to death. A number of marketed medicines consist of active ingredients that may be relatively potent; however, there is plenty of room to enhance their pharmacological profile and therapeutic index by improving specific physicochemical properties. In this work, we focus on a class of blood pressure regulators, called sartans, and we present the computational scheme for the pharmacological improvement of irbesartan (IRB) as a representative example. IRB has been shown to exert increased pharmacological action compared with other sartans, but it appears to be highly lipophilic and violates Lipinski rule (MLogP >4.15). To circumvent this drawback, proper hydrophilic molecules, such as cyclodextrins, can be used as drug carriers. This chapter describes the combinatory use of computational methods, namely molecular docking, quantum mechanics, molecular dynamics, and free energy calculations, to study the interactions and the energetic contributions that govern the IRB:cyclodextrin association. We provide a detailed computational protocol, which aims to assist the improvement of the pharmacological properties of sartans. This protocol can also be applied to any other drug molecule with diminished hydrophilic character.

[1]  Gregory D. Hawkins,et al.  Parametrized Models of Aqueous Free Energies of Solvation Based on Pairwise Descreening of Solute Atomic Charges from a Dielectric Medium , 1996 .

[2]  T. Ruddy,et al.  Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators. , 1998, American journal of hypertension.

[3]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[4]  Karl Nicholas Kirschner,et al.  GLYCAM06: A generalizable biomolecular force field. Carbohydrates , 2008, J. Comput. Chem..

[5]  Tahsin F. Kellici,et al.  Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors , 2015, Molecules.

[6]  R. Skeel,et al.  Langevin stabilization of molecular dynamics , 2001 .

[7]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.

[8]  D. Case,et al.  Exploring protein native states and large‐scale conformational changes with a modified generalized born model , 2004, Proteins.

[9]  Duncan Poole,et al.  Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. , 2013, Journal of chemical theory and computation.

[10]  Daniel R Roe,et al.  PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. , 2013, Journal of chemical theory and computation.

[11]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[12]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[13]  Mushtaq Ahmed,et al.  Molecular Dynamics Simulations, Challenges and Opportunities: A Biologist's Prospective. , 2017, Current protein & peptide science.

[14]  John Hodgson,et al.  ADMET—turning chemicals into drugs , 2001, Nature Biotechnology.

[15]  Guo-jun Zhou,et al.  Comparison of clinical efficacy of metoprolol combined with irbesartan and hydrochlorothiazide and non-invasive ventilator in the emergency treatment of patients with severe heart failure , 2018, Experimental and therapeutic medicine.

[16]  P. Kollman,et al.  Computational study of protein specificity: The molecular basis of HIV-1 protease drug resistance , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Chatzigeorgiou,et al.  Investigation of the interactions of silibinin with 2-hydroxypropyl-β-cyclodextrin through biophysical techniques and computational methods. , 2015, Molecular pharmaceutics.

[18]  Williams E. Miranda,et al.  Computational membrane biophysics: From ion channel interactions with drugs to cellular function. , 2017, Biochimica et biophysica acta. Proteins and proteomics.

[19]  M. Brewster,et al.  Pharmaceutical applications of cyclodextrins: basic science and product development , 2010, The Journal of pharmacy and pharmacology.

[20]  D. Case,et al.  Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. , 2003, Journal of molecular biology.

[21]  M. Karplus,et al.  Molecular dynamics simulations in biology , 1990, Nature.

[22]  B. Rinaldi,et al.  AT1-receptor blockade: Protective effects of irbesartan in cardiomyocytes under hypoxic stress , 2018, PloS one.

[23]  V. Kadam,et al.  Preformulation Study of the Inclusion Complex Irbesartan-β-Cyclodextrin , 2009, AAPS PharmSciTech.

[24]  A. V. D. Vaart.  Coupled binding-bending-folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations. , 2015 .

[25]  T. Mavromoustakos,et al.  Mapping the interactions and bioactivity of quercetin-(2-hydroxypropyl)-β-cyclodextrin complex. , 2016, International journal of pharmaceutics.

[26]  Li Yang,et al.  Irbesartan attenuates advanced glycation end products‐mediated damage in diabetes‐associated osteoporosis through the AGEs/RAGE pathway , 2018, Life sciences.

[27]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[28]  V. Nekkanti,et al.  Insoluble drug delivery strategies: review of recent advances and business prospects , 2015, Acta pharmaceutica Sinica. B.

[29]  J. Berg,et al.  Molecular dynamics simulations of biomolecules , 2002, Nature Structural Biology.