Applications of Quantam Mechanics in Drug Design Quantam mechanics defines the behavior of nuclei and electrons and it also

explains the molecular interactions in terms of distribution and motion. It is necessary to describe the quantized energy levels and to understand the bonding electronic orbitals of atoms and molecules. It is also used in the electrostatic potential energy evaluation directly. Introduction Quantam mechanics is a technique, developed by Erwin Schrodinger, Univ. of Zurich in 1926. It is an important technique for Drug design. Erwin Schrodinger worked out mathematical expressions to describe the motion of an electron in terms of its energy. Those mathematical expressions are called wave equations, since they are based upon the concept that electrons show properties only of particles but also of waves, A wave equation has a series of solutions, called wave functions, each corresponding to a different energy level for the electron. For all but the simplest of systems, doing the mathematics is so time consuming that only solutions can be obtained. Even so, quantum mechanics gives answers agreeing so well with the facts that is accepted today as the

most fruitful approach, to an understanding of atomic and molecular structure. Applications: 1. It is used in the photo-sensitized reactions. 2. It is applied in certain donor-acceptor relationship. certain factors to be considered for donor-acceptor relationships; Donor excited state must have a sufficiently long life time to be able to transfer its energy to the acceptor molecule, it therefore follows the sensitizers will be more effective the more efficient is their inter system crossing. The transfer of energy will occur only if the excitation energy of the former is higher than that of the latter. 3. It is also applied in the synthesis of organic compounds. 4. Photolysis in quantum mechanics are used to describe the breaking of chemical bonds by light energy. 5. Flash photolysis is the process in quantum mechanics is applied in irradiation of reaction mixture. 6. It is also applied in the following photochemical reactions. i) ii) iii) iv) v) Photochemical elimination reactions. Photochemical oxidation reactions. Photochemical cis-trans isomerisms. Photochemical rearrangements. Photochemical cyclisations and intermolecular cyclo

additions. 7. It is applied in intramolecular electrolytic reactions. 8. It is also applied in the preperations of dyes.

Quantum mechanics utilizes a set of mathematical descriptions to define a theoretical model for the behavior of molecules. The validity of these models can be gauged by comparing structures and properties derived from the model with experimental results. In general, ab initio methods are able to reproduce laboratory measurements for properties such as the heat of formation, ionization potential, UV/Visible spectra and molecular geometry. Since quantum methods utilize the principles of particle physics to examine structure as a function of electron distribution, their use can be extended to the analysis of molecules as yet unsynthesized and chemical species which are difficult (or impossible) to isolate. Geometries and properties for transition states (where the electronic character of component atoms is shifting from that found in the starting material to that of the products) and excited states (where the electronic configuration of the molecule is temporarily perturbed by adding energy to the molecule) can only be calculated using quantum methods.

Ab initio quantum methods compute a number of solutions to a

large number of equations. While recent publications have reported calculations on large molecules[1], the methods are generally limited to compounds containing between ten and twenty atoms due to the amount of computer time required for each calculation and the large amount of disk space needed to store intermediate data files. Physical/theoretical chemists have developed alternative approaches to computing structures and properties by simplifying portions of the calculation to circumvent these limitations. These methods are referred to collectively as semiempirical quantum methods. Semiempirical methods utilize approaches which are similar to

ab initio methods, but several approximations are introduced to

simplify the calculations. Rather than performing a full analysis on all electrons within the molecule, some electron interactions are ignored. These methods include the Huckel approach for aromatic compounds (in which the outer electrons in conjugated systems are treated, but the inner (or core) electrons are ignored) and the Neglect of Differential Overlap formalisms found in the CNDO (Complete Neglect of Differential Overlap) and INDO (Intermediate Neglect of Differential Overlap). In these methods, the more complex portions of the ab initio calculation are ignored or set to zero. Other semiempirical approaches replace complex portions of

the calculation with parameters which are derived from experimental data. While semiempirical methods require less computer resources than ab initio methods, they are still compute intensive. In general, calculations are routinely performed on compounds which contain up to 100 atoms. The chief drawback of the method is that its application is limited to systems for which appropriate parameters have been developed. Application of quantum techniques in drug design are detailed in many of the primary journals. Recently, the computational group at Sandoz has reported the use of Gaussian-90 (an ab

initio program) in the analysis of the electronic and tautomeric

factors for a model of H2 receptor agonists[2]. Scientists at The University of San Luis have examined conformational energy maps and electrostatic potentials derived from semiempirical calculations to differentiate between H2 receptor antagonists and H3 receptor agonists[3]. Quantum methods can also be used to examine the forces which determine protein and peptide stability. Sligar and Robinson have reported preparation of the first system which permits measurement of electrostatic effects on the stabilization of helical proteins[4]. D.R. Ripoll and co-workers have utilized calculations from DELPHI (quantum calculations based on

density functional theory) to develop a proposed mechanism for capture of substrate molecules by acetylcholinesterase[5]. Workers at the University of Nancy have used high-level quantum calculations to define six new conformations for peptides. All of the proposed conformations were found in proteins whose structures were solved using X-ray crystallography[6]. 1. Ab Initio Calculations on Large Molecules: Methodology and Applications, Jerzy Cioslowski, in Reviews in Computational Chemistry, VCH Publishers, 1993, vol. 4, Kenny B. Lipkowitz and Donald B. Boyd (editors), pages 1-33. 2. The Computational Design of Amidines as H2Receptor Agonists of Histamine, M. Sabio and S. Topiol, J. Mol. Struct. (Theo Chem), 279, 15-27, 1993. 3. Theoretical Study of Selective H3 Receptor Agonists of Histamine, R.D. Enriz, M.R. Estrada, E.A. Jauregui, C.A. Ponce and F. Tomas-Vert, J. Mol. Struct. (Theo Chem), 280, 5-15, 1993. 4. Electrostatic Stabilization in Four-Helix Bundle Proteins, C.R. Robinson and S.G. Sligar, Protein Science 2, 826-837, 1993. 5. An Electrostatic Mechanism for Substrate Guidance Down the Aromatic Gorge of Acetylcholinesterase, D.R. Ripoll, C.H. Faerman, P.H. Axelsen, I. Silman and J.L. Sussman, Proc. Nat. Acad. Science,

90, 1993.

5128-5132

5128-5132,

6. Peptide Models 6. New b-turn Conformations from ab initio Calculations Confirmed by X-ray data of Proteins, A. Perczel, M.A. McAllister, P. Csarzar and I.G. Csizmadia, J. Amer. Chem. Soc., 115, 4849-4858 1993.