شیمی دارویی کوانتومی

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In The Name of God د 2 

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۱۸ ۶ ۲ Medicinal Chemistry supervisor: by : 3 9 Se 2 

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nal theory -arnaches first- ri phonies 5 ‏ی‎ ntum applications in medicinal Several aGhemistry Bland reviews are available as introduction to the basic theory and to the various flavors of its practical density- -functio (DFT)-based | realization (in terms of different appear ne actual performance of these} functional). : different approximations for diverse chemical and biological systems has been evaluated in a ° ا ی 00000 

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Beyond the capabilities of each of the single parts on their own ۰ A few of these special aspects are ©! summarized schematically in Tab ++ ٠ @ 

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© Limited to accuracy ‘of empirical force © Parameterization ef- fort Q limited transferabil- © MD simulation of © Treatment of transi- tion metal ions dif ficult Tab. 1.1 Comparison of the properties of quantum chemical electronic structure calculations (QC 

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experimenta—\ crystallograph ‏ر‎ yimethods- ~—yandNMR 2 _ new < ‏بت اه‎ (8 3-0 computeraided structure= ame ase ligand- se 

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Density-functional Theory —— 0 0۳0۳۰0۵۷۵002۵1 6۵6۱۵ genomics ‏فررزعزرتعت‎ aut proteomics functional and structural genomic answers to crucial issues related to health and the quality of life. = medicinal 6۳۱6۲۱۱5۲۲۷ the rational mechanism-based approach new therphy ‘rational’ approach : benefiid effects of drugs ~ molecular recognition ۰ binding of ligands to the active site of specific targets enzymes i receptors — nucleic acids 0 201 ا ب د ی عاط د سر تج رای 

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1.۳7 2.AIMD 1.Density-functional Theory Density-functional theory provides a framework to deal with the ground-state energy of the electrons in many-atom systems. the problem of finding the ground-state of a many-electron system consists in finding the lowest energy eigenvalue E and the corresponding eigenstate of the time-independent Schrdinger equation: Hy=Ep (1) late E, one must solve Eq. (2): E=Min,<y|Aly> (2) inimized by means of a normalized vavefunction: 

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ال و | يط ع و وبا روا روا Hohenberg a ۱ ‏از‎ 

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Ab Initio 9 ular Dynan ۳ the int int quantum mechanical A Calculatinne=hacemienn [)F] changes in the 10 

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SAR Studies of Ligand- Target Interactions medicinal chemistry ss of bioactive compounds A key question Determines the variation of biological potency Wit san ofthe series high-throughput methods for determination of the 5 01 

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The Case Study: ار 0 7215256 ‏طيبع‎ 1a: yy ; the pyrimidine 9» is | ۱ ore the oe ts horylation of thymidine (dT) to thymidine ۱ 1 contrast Lule in thd nracanra ar ular TK Herpes aie virus type 1 a EWE — 3211111 a broad range of 

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:Prodrugs Prodrugs are compounds that have to be activated in vivo to achieve the desired pharmacological effect. These prodrugs are selectively aevivated through presphorylation by HSV1 TK to act in their triphosphoryla 

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Bed Ne Aw 0 Despite the clinical success of the antiviral therapy Resistance has emerged as a relevant problem A search for a new prodrug and the design of HSV1 TK mutants with improved specificity A prerequisite for achieving this aim is knowledge at molecular level of substrate binding and Catalysis. 

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Rationalizing Substrate Diversity -S HSV1 TK Ligands ‏إناتائلا‎ ‎Met128 and Tyr172 in N ‏نا‎ dCi herpes simplex vir equine herpes viru varicella zoster vi ١ ‎ee‏ تفاعرت0نا ۰ ‎of the‏ 2۵ دزی ‎thymine with Tyr172 and Met128‏ 

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128, complexes Me Several ‏سا‎ and thymine AIMD The calculations revealed strong Polarization on thymine, but no polarization on the sulfur atom of Met128 H | Neither LUMO 1 the molecular orbitals of | Wet128 an GAP sibs interactions | Met128 an Soe ure Substrale, nor 7-70 interactions | between Tyrl72 and thymine could be observed, | -> Interactions are dominated by electrostatics. hydroge n bonds base within the plane formed of by Met128 and Tyr172 

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HSV1 TK and Substrate Diversity at the Sugar Moiety Level Combined studies Tealving ab initio calculation biochemical and ‏هه مد نهد‎ Sale ‏اون‎ ‎derivatives ott aheugar ۲ ‏و‎ ‎۲۵۵۷۲ ۵۲۱8۵۱95 0 ۷ intetactiotisibetweemuga ee YS nding ‏قح تفت‎ protein ‏ات او زو‎ vanes 01 ‏ار‎ ۳ prodrugs were much smaller than that of the i natura s 

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What Can be Learned from this Case Ctuehs Een CAD ta Aerug Nacian rat Ligands gt _ sco protein-drug interactions functions therapeutics el force- binding free 775 continuum ۱ 15 6 field | methods none enables 3D discrimination 058 between substrate ee new Grugs itors ® discovery 0۲ ‏وم مس‎ 0 prodrug-based DFT-baseg Scoring 

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Theoretical Studies of ۶9 ‏ون وت - و‎ Catalysis Enzymes-are therapeute targets uae molecular level catalytic mecha Ab initio quantum ~. mical calculations _. 

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22 50۰ to the study of enzymajig reactions of phargg وام ۱ Reaction HIV-1 Integra Transition Mey Complexes 

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The Phosphoryl Transfer Reaction Fundamental function ‏اد‎ he cel Caner’ O Hiology: 

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HIV-1 Integr 5 520 Bernardi etal \ DFT reaction mechanic 

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ansition Metal Complexes electrostatic contribution meck. nical meti™ 9 ‏و‎ ‎< better and more 25 هس ‎yay at‏ امرس مس اس و 

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diopharmaceuticals کول ‎okinetics‏ ‎diagnostic or‏ ‎therapeutic‏ med SE ‏یلا‎ ical functi aie nctions 0 ۳ Men imaging design of pew organs ‏رز ممع‎ <7 radiopharmac euticals 6 hw ۳ Yeti} toxic tissues » 

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juantum mecheniqsuter-aided drug research Application of QM ‎LON ras aneanaed‏ 4 اس ‎ ‎ ‎27 

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‎a‏ ع ‎arameterize force orce constants)‏ ‎diagonal ey) ‏۳ : مع ‎a‏ ی ا ‎Hessian is the matrix of second‏ "~~ ‎YY for derivatives of the energy ‎1 quit & small | ‏سک[‎ | ۱ ptimization ‎aw ‎or aad tors ‎geomet 9 ___ good structural ۳ SS accuracy ‎y -4 9 9 freque Cy ca Culat, 2 ‎ ‎ 

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۱6۱9۱۵85 2۱0 ۷۵5 ow بصعصجاء أدداصلعب ۱1| Ore nee ee “oe ‏ججح‎ 

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References: 1. Hiltje, H.- Fecal Folkers, G. in: Methods and Principle in Medicinal Chemistry. R. Mannhold, H. ae, Timmerman (eds), VCH, Weinheim, 1997; 2 ‘h, A. R. in: Molecular modelling. Principles ae appileatons. ‏ام‎ Wesley, 1996. 61-78. 5. Laio, A.;Van de Vondele, J.; Réthlisberger, U. J. 1. Phys. 2002, 116, 6941-6947. lling, P.; Folkers, G.; Scapozza, L. Anal. 2001, 295, 82-87. PA. Acc. Chem. Res.1996, 29, 461- ‎Bae) eo BONN en a aan ee‏ كي لبجو 

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