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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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In The Name of God 1 Quantum Medicinal Chemistry supervisor: by : 2 ory e h t l a n io t c n u f y densit s e h c a o r p p a d e s (DFT)-ba first-princip les quantu m chemical m ethods applications in medicinal chemistry Several excellent text books and reviews are available as introduction to the basic theory and to the various flavors of its practical realization (in terms of different approximations for the exchange-correlation functional). The actual performance of these different approximations for diverse chemical and biological systems has been evaluated in a 3 The Car-Parrinello Approach – Basic Ideas Classical molecular dynamics sche lectronic structure method Orthogonal A series of new features Beyond the capabilities of each of the single parts on their own A few of these special aspects are summarized schematically in Tab 4 Tab. 1.1 Comparison of the properties of quantum chemical electronic structure calculations (QC methods), classical molecular dynamics (Classical MD) based on empirical force fields and first- 5 experimental methods crystallography and NMR new drugs theoretical procedures computeraided molecular design structurebased ligandbased 6 Density-functional Theory Applications in Computational Medicinal Chemistry genomics scientific community proteomics functional and structural genomics answers to crucial issues related to health and the quality of life. medicinal chemistry & the rational mechanismbased approach new therphy ‘rational’ approach : beneficial effects of drugs molecular recognition & binding of ligands to the active site of specific targets enzymes 7 receptors 1.DFT 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 timeindependent Schrِdinger equation: Ĥ (1) To calculate E, one must solve Eq. (2): MinĤ (2) which is minimized by means of a normalized 8 electronic wavefunction: ye d o b y n is a ma n o i t c n u f e v a w c i n lectro depends on the coordinates of all the n elect rons In DFT density (r), depends on one spatial coordinate only Hohenberg and Kohn 9 Ab Initio Molecular Dynamics modeling of atoms in motion characteristics of a ligand-target interaction MD in drug design (MD) simulations empirical force fields describe the interatomic interactions quantum mechanical calculations based on DFT changes in the 10 Car and Parrinello new molecular dynamics scheme potential energy ntaneous ground state of the electrons surface ab initio molecular Model Chemical dynamics(AIMD) with success processes cell functions dynamic AI behavior at finite temper occur at 310 K MD DFT AIMD QM/ MM 11 SAR Studies of Ligand-Target Interactions n medicinal chemistry ass of bioactive compounds A key question Determines the variation of biological potency withinSAR a set analogs ofof the series high-throughput methods for determination of the structure of ligand-macromolecule complexes details at the atomic and electronicexperimental levels are needed data 12 The Case Study: Herpes Simplex Virus Type 1 Thymidine KinaseisSubstrates and Thymidine kinase the key Inhibitors enzyme in the pyrimidine salvage pathway catalyzing the phosphorylation of thymidine (dT) to thymidine monophosphate (dTMP) incontrast the presence of Mg2+ and ATP. cellular TK Herpes simplex virus type 1 thymidine kinase (HSV1 TK) accepts a broad range of 13 :Prodrugs Prodrugs are compounds that have to be activated in vivo to achieve the desired pharmacological effect. These prodrugs are selectively activated through phosphorylation by HSV1 TK to act in their triphosphorylated form: DNA polymerase inhibitors(antiviral compound) DNA chain terminators(prodrug) 14 Chemical formulas of selected (fraudulent) substrates and inhibitors of HSV1 TK (N)MCT, ACV, PCV, GCV, 15 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. 16 Rationalizing Substrate Diversity –SAR of HSV1 TK Ligands The Role of Met128 and Tyr172 in Nucleobase Fixation: herpes simplex virus type 1,2 (HSV 1,2) equine herpes virus type 4 (EHV) varicella zoster virus (VZV) Epstein-Barr virus (EBV) Gln125 was conserved over all species X58/Phe128/ His58/Met128/ Tyr172 EHV, VZV, EBV HSV1, HSV2 the nature of the interactionsab ofinitio DFT calculations thymine with Tyr172 and Met128 17 , 2 7 1 r y T , 8 2 t1 e M s e x Several model comple s n o ti la u im s D IM A e in and thym Aergc1a6lc3u, la Th tionfs th reevceoam . x le p le d s t r o ong polarization y it il b taine onthtehysm , but no polarizatio n on the sulfur atom of Met128 HOMOLUMO gap hydrogen bonds d e m r fo e n la p e th in h it base w by Met128 and Tyr172 18 HSV1 TK and Substrate Diversity at the Sugar Moiety Level Combined studies involving ab initio calculation biochemical and tructural characterization using thymine fundamental questions derivatives with aof sugar about the nature the moiety HSV1 TK hasbetween no selectivity for the conformation interactions of the sugar moiety. the ribose-like moiety and the enzyme were -bonding interactions protein- very still unanswered. sugar similar why the kcat values of prodrugs were much smaller than that of the 19 initio DFT-based calculations natural substrate What Can be Learned from this Case Study From SAR to Drug Design rational Ligands design virtual new scoring protein-drug interactions screening therapeutics functions forcefield continuum methods none enables 3D discrimination QSAR between substrate s g and inhibitors u r d w e n f o y r DFT-based scoring discove prodrug-based function DFT-based 20 scoring Theoretical Studies of Enzymatic Catalysis Enzymes are therapeutic targets many drugs molecular level inhibiting All the techniques s t r u c t u re Pauling theory c a t a l y t i c mechanisms .Michaelis complex the powerful catalytic action of the sical methods furnishing information enzymes might be explained by specific S of binding enzymatic atomic level of reactions the enzymes to the TS Ab initio quantum chemical calculations 21 some recent applications of DFT to the study of enzymatic reactions of pharmaceutical interest: The Phosphoryl Transfer Reaction HIV-1 Integrase Transition Metal Complexes 22 The Phosphoryl Transfer Reaction Fundamental functions of the cell some pathology AIMD simulation DFT-based Car-Parrinello (CPMD) effects of finite temperature biological systems 23 HIV-1 Integrase a class of enzymes viral DNA host-cell nucleus Bernardi et al DFT B3LY P 6311G(d ,p) G98 reaction 24 Transition Metal Complexes modeling of transition metal complexes by computational methods based s on classical n o i t a l u c l tio ca i n i b a molecular Determination of mechanics the effect of important c hemical and ph ysical fea electrostatic contribution Quantum mechanical D methods 25 FT better and more adiopharmaceuticals pham etaacl o rm om kcin etpiclsexes i e l c u n e diagnostic or v i t c a o i rad therapeutic procedure medicine to che monm itoicrabl iologica l functions enviro nment w organs imaging of tissues and e n f o n g i s e d compoundnsew cancer radiopharmace diagnosis uticals ent of l b a t s e e r tm o a e m tr icues x o t s s e l s s ti d s 26 caanncerou Quantum mechanics computer-aided drug research : Application of QM calculation of atomic point charges hydrogen bonding Intermolecular Coulomb forces molecular electrostatic potentials MEP to find a biologically relevant conformation for ulcer therapy 27 The most important application of QM is explicit description of the electronic modeling structure Biological of a molecule interaction studies targets of drugs recep enzy mes tors molecular mechanics molecules : a collection methods of atoms held together by elastic or potential harmonic Structural forces energy features functions bond lengths bond angles torsional angles non-bonded interactions28 n a m h s A d n a ts n a t s d n o c r e c r fo a e z i r e t n e m a r o a e method to p di agonal elemen ts of an ab initi o Hessi Hessian is the matrix of second only fo derivatives of the energy r quite small m olecul es tion a z i m i t p o geometry good structural accuracy a frequen cy calcula tion 29 onclusions and Perspectives ns calculatio Application of quantum mechanics Quantu m Tool in medicinal chemistry theory ” “reality Development supercomputers mole cular mo delin g complement experimental measurements DFT-based methods reliability and suitability theoretical medicinal chemistry 30 to increase the use of quantum chemical calculation within medicinal chemistry the size of the systems studied must be enlarged DFT QM/ MM the precision of quantum chemical calculation the power of molecular mechanics 31 References: 1. Höltje, H.-D.; Folkers, G. in: Methods and Principle in Medicinal Chemistry. R. Mannhold, H.K.H. Timmerman (eds), VCH, Weinheim, 1997; Vol. 5. 2. Leach, A. R. in: Molecular modelling. Principles and applications, Addison Wesley, 1996. 3. Vedani, A.; Zbinden, P.; Snyder, J. P.; Greenidge, P. A. J. Am. Chem. Soc. 1995, 117, 4987–4994. 4. Bohm, H.J. J. Comput. Aid. Mol. Des. 1992, 6, 61–78. 5. Laio, A.;Van de Vondele, J.; Röthlisberger, U. J. Chem. Phys. 2002, 116, 6941–6947. 6. Schelling, P.; Folkers, G.; Scapozza, L. Anal. Biochem. 2001, 295, 82–87. 7. Kollman, P. A. Acc. Chem. Res.1996, 29, 461–469. 8. Olson, M.F.; Ashworth, A.; Hall, A. Science 1995, 269, 1270–1272. 32 9. Wittinghofer, A. Curr. Biol. 1997, 7, R682–R685 33