molecular and quantum mechanics in drug design 1 · quantum mechanics and molecular mechanics there...
TRANSCRIPT
![Page 1: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/1.jpg)
.
![Page 2: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/2.jpg)
INTRODUCTION
� Drug discovery and developing a new medicine is a long, complex, costly and highly risky process that has few peers in the commercial world.
� This is why computer-aided drug design (CADD) approaches are being widely used in the pharmaceutical industry to accelerate the process.
� On an average, it takes 10-15 years and US $500-800 million to introduce a drug into the market, with synthesis and testing of lead analogs being a large contributor to that sum.
![Page 3: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/3.jpg)
� Therefore, it is beneficial to apply computational tools inhit-to-lead optimization to cover a wider chemical spacewhile reducing the number of compounds that must besynthesized and tested in vitro.
� CADD is capable of increasing the hit rate of novel drug� CADD is capable of increasing the hit rate of novel drugcompounds because it uses a much more targeted searchthan traditional high throughput screening (HTS) andcombinatorial chemistry.
� It not only aims to explain the molecular basis oftherapeutic activity but also to predict possible derivativesthat would improve activity.
![Page 4: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/4.jpg)
CADD is usually used for three major purposes :
� filter large compound libraries into smaller sets of� filter large compound libraries into smaller sets of
compounds that can be tested experimentally ,
� guide the optimization of lead compounds, to increase itsDMPK properties including ADMET;
� design novel compounds, either by "growing" startingmolecules one functional group at a time or by piecingtogether fragments into novel chemotypes.
![Page 5: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/5.jpg)
CADD can be classified into two general categories :
1. Structure based
2. Ligand based
� Structure-based CADD relies on the knowledge of thetarget protein structure to calculate interaction energiestarget protein structure to calculate interaction energiesfor all the compounds to be tested,
� Structure based CADD is generally preferred wherehigh-resolution structural data of the target protein areavailable,
� whereas ligand-based CADD exploits the knowledge ofknown active and inactive molecules through chemicalsimilarity searches or construction of predictive,quantitative structure-activity relationship
![Page 6: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/6.jpg)
� Ligand based CADD is generally preferred when no or littlestructural information is available, often for membraneprotein targets.
� The central goal of structure based CADD is to designcompounds that bind tightly to the target, i.e., with largerreduction in free energy, improved DMPK/ADMETproperties, and are target specific .properties, and are target specific .
![Page 7: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/7.jpg)
![Page 8: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/8.jpg)
![Page 9: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/9.jpg)
RECEPTOR THEORY� Paul Ehrlich at the turn of the 19th century as part of the
now seminal "lock and key" hypothesis.
� This hypothesis has described drugs as receptor’s ligands orenzyme substrates that selectively modulate the functionof unknown molecular targets to produce beneficial effects.
� Michaelis and Menten in 1913.
Receptor + Ligand [RL] R + Cellular Effect ... (1)
� The ligand L binds to the receptor R and alters the natureof the receptor interaction with its associated membranecomponents to effect a change in cellular and ultimately,tissue function.
![Page 10: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/10.jpg)
� Ligands interacting with the receptors have two intrinsic properties: Affinity and Efficacy
� Affinity is the ability to recognize and bind to the receptor.
� Ability of the ligand to produce changes in receptor and produce a response is Efficacy.
� It is clear that a biological response is produced by the interaction of a drug with the biological receptor. This interaction of a drug with the biological receptor. This selective binding and its extent is governed by the molecular recognition phenomenon.
� In molecular modeling, this process of molecular recognition is simulated to understand the drug- receptor interaction .
� In molecular modeling every effort is made to measure the free energy of association (ΔG).
![Page 11: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/11.jpg)
Quantum Mechanics and Molecular Mechanics
� There are two different approaches to compute the energy of a molecule.
� Quantum mechanics - In this approach, nuclei arearranged in the space and the corresponding electrons arearranged in the space and the corresponding electrons arespread all over the system in a continuous electronicdensity and computed by solving the Schrödingerequation.
![Page 12: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/12.jpg)
� This mathematical model is known as molecularmechanics, and can be used to compute the energy ofsystems containing a large number of atoms, such asmolecules or complex systems of biochemical andbiomedical interest.
� In contrast to quantum mechanics, molecular mechanicsignore electrons and compute the energy of a system onlyignore electrons and compute the energy of a system onlyas a function of the nuclear positions.
![Page 13: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/13.jpg)
![Page 14: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/14.jpg)
![Page 15: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/15.jpg)
![Page 16: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/16.jpg)
FORCE FIELD� In molecular mechanics the electrons and nuclei of the
atoms are not explicitly included in the calculations
� A force field refers to the functional forms and parameter sets used to calculate the potential energy of the system of atoms in molecular mechanics.
� it consists of a sum of different contributions that compute the deviations from equilibrium of bond lengths, angles, torsions and non-bonded interactions
![Page 17: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/17.jpg)
� where E-total is the total energy of the molecule, E-stretching is the bond-stretching energy term, E-bending isthe angle-bending energy term, E-torsion is the torsionalenergy term, E-vander wall is the van der Waals energyterm, and E-elec is the electrostatic energy term.
� Each deviation from these equilibrium values will result inincreasing total energy of the molecule.increasing total energy of the molecule.
� the total energy is a measure of intramolecular strainrelative to a hypothetical molecule with an ideal geometryof equilibrium .
![Page 18: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/18.jpg)
Energy-Minimizing Procedures 1. Steepest Descent Method
2. Conjugate Gradient Method
![Page 19: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/19.jpg)
Structure-Based Computer-Aided Drug Design
� Structure-based computer-aided drug design (SBDD) relieson the ability to determine and analyse 3D structures ofbiological molecules
� The core hypothesis of this approach is that a molecule’sability to interact with a specific protein and exert a desiredability to interact with a specific protein and exert a desiredbiological effect depends on its ability to favourablyinteract with a particular binding site on that protein
� novel compounds can be elucidated through the carefulanalysis of a protein’s binding site.
![Page 20: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/20.jpg)
Example of Marketed Drugs Involving use of Structure based Drug Design.
![Page 21: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/21.jpg)
Preparation of a Target Structure � Success of virtual screening depends upon the amount
and quality of structural information known about both the target and the small molecules being docked
� The first step is to evaluate the target for the presence of an appropriate binding pocketof an appropriate binding pocket
� This is usually done through the analysis of known target-ligand co-crystal structures or using in-silicomethods to identify novel binding sites.
� A target structure experimentally determined through X-ray crystallography or NMR techniques.
![Page 22: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/22.jpg)
HOMOLGY MODELLING
![Page 23: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/23.jpg)
![Page 24: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/24.jpg)
![Page 25: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/25.jpg)
Ligand-Based Computer-Aided Drug Design
� The ligand-based computer-aided drug discovery (LBDD) approach involves the analysis of ligands known to interact with a target of interest
� These methods use a set of reference structures collected � These methods use a set of reference structures collected from compounds known to interact with the target of interest and analyse their 2D or 3D structures.
� It is considered as an indirect approach to the drug discovery in that it does not necessitate knowledge of the structure of the target of interest.
![Page 26: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/26.jpg)
The two fundamental approaches of LBDD are :
1. selection of compounds based on chemical similarity toknown actives using some similarity measure
2. the construction of a quantitative structure activityrelationship (QSAR) model that predicts biological activityfrom chemical structure .from chemical structure .
� The methods are applied for in silico screening for novelcompounds possessing the biological activity of interest, hit-to-lead and lead-to drug optimization, and also for theoptimization of DMPK/ADMET properties.
� Additionally, active compounds identified by ligand-basedvirtual high-throughput screening (LB-vHTS) methods areoften more potent than those identified in SB-vHTS.70
![Page 27: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/27.jpg)
REFERENCE
� 1. Basak SC. Chemobioinformatics: the advancing frontier of computer-aided drug design in the post-genomic era. Curr. Comput. Aided. Drug. Des. 2012;8:1-2.
� 2. Enyedy IJ and Egan WJ. Can we use docking and scoring for hit-to-lead optimization? J. Comput. Aided. Mol. Des. 2008;22:161-168. optimization? J. Comput. Aided. Mol. Des. 2008;22:161-168.
� 3. Veselovsky AV, Ivanov AS. Strategy of computer-aided drug design. Curr. Drug. Targets. Infect. Disord. 2003;3:33-40.
� 4. Kalyaanamoorthy S and Chen YP. Structure-based drug design to augment hit discovery. Drug. Discov. Today. 2011;16:831-839.
� 5. Jorgensen WL. Drug discovery: Pulled from a protein’s embrace. Nature. 2010;466:42-43.
� 6. Lombardino JG, Lowe JA. The role of the medicinal chemist in drug discovery then and now. Nat. Rev. Drug. Discov. 2004;3:853-62.
� 7. Gershell LJ, Atkins JH. A brief history of novel drug discovery technologies. Nat. Rev. Drug. Discov. 2003; 2:321-327
![Page 28: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/28.jpg)
� 9. Michaelis L, Menten ML. The original Michaelis constant: translation of the 1913 Michaelis-Menten paper. Biochem.1913;49:333-369.
� 10. Williams M, Deecher DC, Sullivan JP. Burger’s Medicinal Chemistry and Drug Discovery, Wolff, M. E. (Ed.), Vol. I, Wiley Interscience.1995, 349-359.
� 11. Wold F. In Macromolecules: Structure and Function. Cliffs, E. (Ed.), Prentice-Hall, New Jersey, 1971, 16-40.
� 12. Albert, A. In Selective Toxicity. Wiley, New York, 1968, 183. � 13. Pensak DA. Molecular modelling: scientific and technological boundaries.
Pure & Appl. Chem.1989;61:601. Pure & Appl. Chem.1989;61:601. � 14. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus
M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J. Comput. Chem. 1983;4:187-217.
� 15. Hagler AT, Lifson S, Dauber P. Consistent force field studies of intermolecular forces in hydrogen bonded crystals. II. A benchmark for the objective comparison of alternative force fields. J. Am. Chem. Soc. 1979;101:5122-5130.
![Page 29: MOLECULAR AND QUANTUM MECHANICS IN DRUG DESIGN 1 · Quantum Mechanics and Molecular Mechanics There are two different approaches to compute the energy of a molecule. Quantum mechanics](https://reader036.vdocuments.us/reader036/viewer/2022062506/5f8b58077de61a4cae528a4f/html5/thumbnails/29.jpg)