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Prediction of molecular properties (I) The general question of rational drug design Wow is the biological space (activity) of a compound connected to the chemical space (structure) ? Is it possible to make predictions based on the molecular structure ? QSAR and QSPR 12th lecture Modern Methods in Drug Discovery WS06/07 1 Prediction of molecular properties (II) observables What are molecular properties? 12th lecture molecular weight MW (from the sum formula C12H11N3O2) melting point boiling point vapour pressure solubility (in water) charge dipole moment Directly computable from the electronic polarizability wave function of a ionization potential molecule electrostatic potential Modern Methods in Drug Discovery WS06/07 2 Prediction of molecular properties (III) All molecular properties that can be measured by physicochemical methods (so called observables) can also be comouted directly by quantum chemical methods. Required: A mathematical description of the electron distribution e.g. by the electronic wave function of the molecule 12th lecture Electron distribution Quantum mechanics (QM) Atomic coordinates Molecular mechanics (MM) force fields Modern Methods in Drug Discovery WS06/07 3 Quantum mechanics (I) To make the mathematical formalism practically useable, a number of approximations are necessary. One of the most fundamental consists in separating the movement of the atomic cores from that of the electrons, the so called Born-Oppenheimer Approximations: Atomic cores are > 1000 times heavier than the electrons und thus follow the movements of the faster electrons. The (electrostatic) interaction between charged particles (electrons, cores) is expressed by Coulomb‘s law qi Vij rij qj 12th lecture qi q j rij Modern Methods in Drug Discovery WS06/07 4 Quantum mechanics (II) As electrons are particles, their movement can be described by classical mechanics according to Newtons 2nd law: F ma dV 2r m dr t As electrons are also very small particles (quants), they exhibit properties of particles as well as those of waves: 12th lecture particle wave galvanic precipitation diffraction Modern Methods in Drug Discovery WS06/07 5 Schrödinger equation (I) Electrons can be described in the form of a wave function by the time-dependent Schröder equation H i t If the Hamilton operator H is time-independent, the timedependence of the wave function can be separated as a phase factor, which leads to the time-independent Schrödinger equation. Here, only the dependence from the coordinates remains. r, t r e i E t / H r E r 12th lecture Modern Methods in Drug Discovery WS06/07 6 The wave function (I) The wave function is a mathematical expression describing the spacial arrangement of the (fluctuating) electrons. The squared wave function holds the propability P to find the particle (electron) at a given place in space. P P is a so-called observable, whereas the wave function itself is no observable, physical quantity. Thus, integration over the complete space must yield 1 (= total propability to find it somewhere in space). d 1 12th lecture Modern Methods in Drug Discovery WS06/07 7 The Hamilton operator The Hamilton operator contains the kinetic (T) and the potentiell (V) energy of all considered particles i in the system 2 2 T Ti i i 1 i 1 2mi N H TV N with the squared Nabla operator 2 2 2 2 i 2 2 2 xi yi zi N N V Vij i 1 j i with Vij qi q j rij As a consequence of the Born-Oppenheimer approximation, also the Hamilton operator can be sepatared into a core and an electronic part. 12th lecture Modern Methods in Drug Discovery WS06/07 8 The wave function (II) Any mathematical expression of the wave function must fulfill certain criteria to account for the physical nature of the electrons. As a simplification the wave function of all electrons in a molecule is assumed to be the product of one-electron functions which themselves describe a single electron. 1 2 ... N These function must fulfill some criteria: • electrons are indistinguisable • The repell each other • The Pauli principle (two electrons with different spin can share a common state (orbital)) 12th lecture Modern Methods in Drug Discovery WS06/07 9 Schrödinger equation (II) According to the Schrödinger equation there must be several different energetic levels for the electrons within an atom or molecule. These (orbital) energies can be obtained by integration and rearrangement to 2 H d E d H d E d 2 The resulting energies are, however, dependend on the quality of the applied wave function and thus always higher or, in the best case, equal to the actual energy. In the simplest case we chose 1s orbitals as basis set to describe the wave function 12th lecture Modern Methods in Drug Discovery WS06/07 10 Molecular Orbital Theory (I) Molecular orbitals can be constructed as a linear combination of atomic orbitals (LCAO approach) or other basis functions. cA A cB B ... c N N e.g. for H2 cA1sA cB1sB 1sA 1sB K Common expression for a MO with the atomic orbitals 12th lecture i c i 1 Modern Methods in Drug Discovery WS06/07 11 Molecuar Orbital Theory (II) Applying the LCAO approach for the wave function we yield for H2 2 d cA A cB B cA A cB B d c 2A A2 c 2B B2 2c A c B A B d c 2A A2 d c 2B B2 d 2c A c B A Bd =1 =1 overlap intergral S Due to the normalization of the wave function regarding the complete space: 2 2 2 d c c A B 2c A c BS 12th lecture Modern Methods in Drug Discovery WS06/07 12 Molecular Orbital Theory (III) Common notation of the Sekular equations using matrices: H ES 0 The solutions of these Sekular equations for E yield the energies of the bonding and anti-bonding MOs E 0 The main numerical effort consists in the iterative search for suitable coefficients (cA, cB, ...) that produces reasonable orbital energies variational principle Hartree-Fock equations Self Consistent Field (SCF) method 12th lecture Modern Methods in Drug Discovery WS06/07 13 Hückel Theory (I) (1931) Limited to planar, -orbitale are neglected. conjugated -systems, The original aim was to interpret the non-additive properties of aromatic compounds (e.g. benzene compared to “cyclohexatrien”) regarding their heats of combustion. The -orbitals are obtained as linear combinations of atomic orbitals (LCAO of pz-orbitals). The -electrons move in an electric field produced by the -electrons and the atomic cores. 12th lecture Modern Methods in Drug Discovery WS06/07 14 Hückel Theory (II) Example ethene H2C=CH2 E pz pz 12th lecture Modern Methods in Drug Discovery WS06/07 15 Hückel Theory (III) Within the Hückel theory the Fock matrix contains as many columns, respectively rows, as atoms are present in the molecule. All diagonal elements correspond to an atom i and are set to the value . Offdiagonal elements are only non-zero if there is a bond between the atoms i and j. This resonance parameter is set to (<0). Values for can be obtained experimentally from UV/VIS-spectra ( -4.62 eV). Example butadiene: 1 2 3 4 2 1 12th lecture 4 3 1 0 0 2 0 3 0 4 0 0 Modern Methods in Drug Discovery WS06/07 16 Hückel Theory (IV) For a cyclic -system as in benzene, the orbital energies and orbital coefficients results to 2k ; with k 0,1,..., N 1 N 2 1k 1 ci exp N N i 2 cos E 0 This also yields the Hückel rule, where a system of [4n+2] -electrons is aromatic. 12th lecture Modern Methods in Drug Discovery WS06/07 17 Hückel Theory (V) • Application of the Hückel method to predict and interpret UV/VIS spectra • Different parameters for different atoms (C,N,O) allow the application of the Hückel theory to further compounds • Orbital energies can be determined experimentally by photo electron spectroscopy (PES) and thus also (the respective ionization potential) and 12th lecture Modern Methods in Drug Discovery WS06/07 18 Hartree-Fock based methods H = E Born-Oppenheimer approximation one-determinant approach ZDO-approximation valence electrons parameters Hartree-Fock-equations optimized basis sets RHF semiempirical methods with minimal basis set all electron ab initio methods with limited basis set multi-determinant approaches UHF Valence electrons ECP spin (,) space semiempirical C.I. methods 12th lecture CI MCSCF Modern Methods in Drug Discovery WS06/07 CASSCF 19 Semiempirical methods (I) The problem of ab initio calculation is their N4 dependence from the number of two-electron integrals. These arise from the number of basis functions and the interactions between electrons on different atoms. In semiempirical methods the numerical effort is strongly reduced by assumptions and approaches: 1. Only valence electrons are considered, the other electrons and the core charge are described by an effective potential for each atom (frozen core). 2. Only a minimal basis set is used (one s and three p-orbitals per atom), but using precise STOs that are orthogonal to each other. 3. More or less stringent use of the Zero Differential Overlap (ZDO) approach. 12th lecture Modern Methods in Drug Discovery WS06/07 20 Semiempirical methods (II) Since 1965 a series of semiempirical methods has been presented from which still some are in use today for the simulation of electromagnetic spectra: CNDO/S, INDO/S, ZINDO Following methods have shown to be particularly successful in predicting molecular properties: MNDO (Modified Neglect of Diatomic Overlap) Thiel et al. 1975, AM1 (Austin Model 1) Dewar et al. 1985 und PM3 (Parameterized Method 3) J.P.P. Stewart 1989 This partly also due to their availability of the wide spread MOPAC program package and its later commerical sucessors. All three method are based on the same NDDO approach and differ in the respective parameterization of the respective elements. 12th lecture Modern Methods in Drug Discovery WS06/07 21 AM1 (Austin Model 1) Dewar, Stewart et al. J.Am.Chem.Soc. 107 (1985) 3902 Advantages compared to MNDO: + better molecular geometries esp. for hypervalent elements (P, S) + H-bonds (but with a tendency towards forking) + activation energies for chemical reactions Deficiencies of AM1 (and all other methods based on NDDO): - hypervalent elements in general, because no d-orbitals - compounds with lone electron pairs (esp. anomeric effect) - NO2 containing compounds 12th lecture Modern Methods in Drug Discovery WS06/07 22 PM3 (Parameterized Method 3) J.J.P. Stewart J.Comput.Chem. 10 (1989) 209 Parametrization was performed more rigerously using errror minimization than in previous methods. Advantages compared to AM1: + better molecular geometries for C, H, P and S + NO2 containing compounds better Disadvantages compared to AM1: - All other nitrogen containing compounds worse - higher atomic charges lead to a more polar character of the molecules - Not all parameterized elements (e.g. Mg and Al) yield reliable results for all substance classes 12th lecture Modern Methods in Drug Discovery WS06/07 23 Molecular properties from semiempirical QM calculations (I) In contrast to ab initio calculations the semiempirical methods MNDO, AM1, and PM3 were calibrated to reproduce experimental data: • heats of formation [Bildungswärmen] • molecular geomtries (bond lengths, bond angles) • dipole moments • ionization potentials The results of semiempirical methods regarding these properties are therefore often better than that of ab initio calculations at low level (with comparable computational effort) 12th lecture Modern Methods in Drug Discovery WS06/07 24 Heats of formation Computation of heats of formation at 25° C H f o (molecule ) E elec (molecule ) atoms E elec (atoms) atoms H fo (atoms) atomization Heats of formation energies of the elements Experimentally known Only the electronic energy has to be computed O H 12th lecture O atomization H H Eelec(molecule) H Modern Methods in Drug Discovery WS06/07 O H H 25 Comparison of the methods Calculated heats of formation at 25° C for different compounds Average mean error (in kcal/mol) Number of compounds method (C, H, N, O, and) MNDO AM1 PM3 Al (29) 22.1 10.5 16.4 4.9 Si (84) 12.0 8.5 6.0 6.3 P (43) 38.7 14.5 17.1 7.6 S (99) 48.4 10.3 7.5 5.6 Cl (85) 39.4 29.1 10.4 3.9 Br (51) 16.2 15.2 8.1 3.4 I (42) 25.4 21.7 13.4 4.0 Zn (18) 21.0 16.9 14.7 4.9 Hg (37) 13.7 9.0 7.7 2.2 Mg (48) 9.3 15.4 12.0 9.3 12th lecture Modern Methods in Drug Discovery WS06/07 MNDO/d 26 New semiempirical methods since 1995 MNDO/d Thiel & Voityuk J.Phys.Chem. 100 (1996) 616 Expands the MNDO methods by d-obitals and is “compatible” with the other MNDO parameterized elements PM3(tm), PM5 d-orbitals for transition elements (transition metals) SAM1 Semi ab initio Method 1 Certain integrals are thouroghly computed, therefore also applicable to transition metals (esp. Cu and Fe) AM1* Winget, Horn et al. J.Mol.Model. 9 (2003) 408. d-orbitals for elements from the 3rd row on (P,S, Cl) 12th lecture Modern Methods in Drug Discovery WS06/07 27 Electronic molecular properties (I) Besides the structure of molecules all other electronic properties can be calculated. Many of those results as response of the molecule to an external disturbance: Removal of one electron ionization potential In general a disturbance by an electric field can be expressed in the form of a Taylor expansion. In the case of an external electrical field F the induced dipole moment ind is obtained as: ind o F 12 F 2 ... o permanent dipol moment of the molecule (if present) polarizability (first) hyperpolarizability 12th lecture Modern Methods in Drug Discovery WS06/07 28 Electronic molecular properties (II) Selection of properties that can be computed from the n-th derivative of the energy according to external fields electr. magn. nuc.spin coord. property 0 1 0 0 0 2 3 0 1 1 0 0 energy electric dipol moment magentic dipol moment hyperfine coupling constant (EPR) energy gradient (geom.optimization) electric polarizability (first) hyperpolarizability harmonic vibration (IR) IR absorption intensities circular dichroisms (CD) nuclear spin coupling const. (NMR) nuclear magnetic shielding (NMR) 12th lecture 0 0 1 0 0 0 0 0 0 1 0 1 0 0 0 1 0 0 0 0 0 0 2 1 0 0 0 0 1 0 0 2 1 0 0 0 Modern Methods in Drug Discovery WS06/07 29 Molecular electrostatic potential (I) Due to the atomic cores Z and the electrons i of a molecule a spacial charge distribution arises. At any point r the arising potential V(r) can be determined to: VESP r cores A ri 2 ZA dri r RA r ri While the core part contains the charges of the atomic cores only, the wave function has to be used for the electronic part. Remember: In force fields atomic charges (placed on the atoms) are used to reproduce the electric multipoles and the charge distribution. 12th lecture Modern Methods in Drug Discovery WS06/07 30 Molecular electrostatic potential (II) To determine the MEP at a point r the integration is practically replaced by a summation of sufficiently small volume elements. For visualization the MEP is projected e.g. onto the van der Waals surface. Other possibilities are the representation of surfaces with the same potential (isocontour) From: A. Leach, Molecular Modelling, 2nd ed. 12th lecture Modern Methods in Drug Discovery WS06/07 31 Molecular electrostatic potential (III) Knowledge of these surface charges enables computation of atomic charges (e.g. for use in force fields) ESP derived atomic charges These atomic charges must in turn reproduce the electric multipoles (dipole, quadrupole,...). Therefore the fitting procedures work iteratively. literature: Cox & Williams J.Comput.Chem. 2 (1981) 304 Bieneman & Wiberg J.Comput.Chem. 11 (1990) 361 CHELPG approach Singh & Kollman J.Comput.Chem. 5 (1984) 129 RESP approach atomic charges for the AMBER force field 12th lecture Modern Methods in Drug Discovery WS06/07 32 Quantum mechanical descriptors (selection) atomic charges (partial atomic charges) No observables ! Mulliken population analysis electrostatic potential (ESP) derived charges E dipole moment LUMO polarizability HOMO HOMO / LUMO of the frontier orbitals WienerJenergies (Pfad Nummer) given in eV Donor Akzeptor covalent hydrogen bond acidity/basicity difference of the HOMO/LUMO energies compared to those of water Lit: M. Karelson et al. Chem.Rev. 96 (1996) 1027 12th lecture Modern Methods in Drug Discovery WS06/07 33 Molecular properties from semiempirical methods (II) Which method for which purpose ? strutural properties only (molecular geometries): PM3 esp. for NO2 compounds electronic properties: MNDO for halogen containing compounds (F, Cl, Br, I) AM1 for hypervalent elements (P,S), H-bonds Do not mix descriptors computed from different semiempirical methods ! E.g. PM3 for NO2 containing molecules and AM1 for the remaining compounds in the set. 12th lecture Modern Methods in Drug Discovery WS06/07 34 Prediction of Molecular Properties, Examples Descriptors from semiempirical methods (ionization potential, dipole moment ...) along commonly used variables in QSAR equations and classification schemes. Often much more qualitative experimental data than quantitative date are available. • in vitro mutagenicity of MX compounds • Blood-brain distribution (logBB) • CNS permeability of substances • QT-interval prolongation (hERG channel blockers) 12th lecture Modern Methods in Drug Discovery WS06/07 35 Quantum QSAR Generation of molecular properties as descriptors for QSARequations from quantum mechanical data. Example: mutagenicity of MX compounds Cl2CH Cl R2 H R1 H O ln TA100 [ revertants/nmol ] O HO 10 O R3 O 8 6 O O 4 2 0 -2 ln(TA100) = -13.57 E(LUMO) –12.98 ; r = 0.82 -4 -6 -8 -0.3 -0.5 -0.7 -0.9 -1.1 -1.3 -1.5 E(LUMO) AM1 calculation [ eV ] Lit.: K. Tuppurainen et al. Mutat. Res. 247 (1991) 97. 12th lecture Modern Methods in Drug Discovery WS06/07 36 BBB-model with 12 descriptors Descriptors mainly from QM calculations: electrostatic surface, principal components of the geometry, H-bond properties 2.5 r2=0.866, adj. r2=0.844, se=0.308, n=90 predicted logBB 1.5 0.5 -0.5 -1.5 -2.5 -2.5 -1.5 -0.5 0.5 1.5 2.5 observed logBB Lit: M. Hutter J.Comput.-Aided.Mol.Des. 17 (2003) 415. 12th lecture Modern Methods in Drug Discovery WS06/07 37 CNS Permeability 95% CNS– 91% CNS+ 82% hlsurf 99% 72% vxbal 99% qsum+ qsumo ar5 96% 96% qsum+ qsum+ 12th lecture 89% 100% 100% 100% 100% 88% qsum– 100% pcgc 100% qsum– mpolar 79% 100% 89% 77% cooh 83% dipdens 89% qsum– 80% hbdon size & shape 99% qsum+ 86% dipm electrostatic H-bonds mde34 100% 100% 100% 100% 100% 100% 100% kap3a 92% mde13 Modern Methods in Drug Discovery WS06/07 Lit.: C.Andres & M.Hutter QSAR Comb.Sci. 25 (2006) 305. 100% 94% 38 Decision tree for QT-prolonging drugs 89% size & shape 88% electrostatic 75% 73% H-bonds hacsurf 86% 71% 99% QT+ QT– t1e 88% Level of accuracy in % 12th lecture MR mde23 100% 100% 100% logP 100% 100% qsumn 100% 100% MR 100% 92% 83% MR 100% t2e 99% 93% MR 100% 96% mpolar sgeca 95% 87% dipdens 82% 89% 96% 89% SMARTS 90% 100% chbba hlsurf hy mghbd logP MR Modern Methods in Drug Discovery WS06/07 96% qsumn 100% 100% 100% 100% 39 Common structural features of QT-prolonging drugs F NH2 Cl F O H N Cl N O HO O N N H OH N O N O N N N HO N F O N N O N N O Astemizole H Sertindole H F Terfenadine Cisapride Grepafloxacin Derived common substructure expressed as SMARTS string Lit.: M.Gepp & M.Hutter Bioorg.Med.Chem. 14 (2006) 5325. 12th lecture Modern Methods in Drug Discovery WS06/07 40 Molecular properties from force fields As as principal consequence force fields show an even more emphasized dependence from the underlying parameterization. Thus only predictions regarding structure ( docking), dynamics ( molecular dynamics) and, rather limited, about spectra (vibrational Infra Red) can be made. Due to the low computational effort, force fields are well suited to allow conformational searches. 4D-QSAR (different docked conformations, e.g. in cytochrome P450) 12th lecture Modern Methods in Drug Discovery WS06/07 41 Molecular properties from molecular dynamics simulations Binding affinities (actually free energies of binding) G for ligand binding to enzymes from free energy perturbation calculations Advantage: quite precise predictions Disadvantage: computationally very demanding, thus only feasible for a small number of ligands Lit.: A.R. Leach Molecular Modelling, Longman. 12th lecture Modern Methods in Drug Discovery WS06/07 42