Quantum Chemistry Calculations Of Halogen Bonding,Guanidinium-Arginine Interactions And Transition State Of Drug Synthetic Reactions In Drug Design

Quantum chemistry is the application of quantum mechanics to the study of chemical phenomena,which is rapidly emerging as a universal technique and means of description and prediction of molecule structure and chemical behavior in chemistry and other related disciplines.This thesis is composed of two parts;the first part is mainly focused on the research of application of quantum chemistry calculation methods in drug design,including the second chapter on the intramolecular halogen bonding,the third chapter on the guanidinium-arginine pairing in biological systems and the fourth chapter on the reaction mechanism in drug synthesis.The second part(the fifth chapter)is focused on the discovery of inhibitor of dihydrofolate reductase(DHFR)for Mycobacterium tuberculosis(Mtb).We used two approaches,including molecular docking and mass spectrometry,for the prediction and validation of natural product inhibitors for this important drug target of tuberculosis.The first chapter is the introduction,which describes the research background of quantum chemical calculations of noncovalent interactions,halogen bonding in drug design and fragment-based drug design of tuberculosis.The second chapter focuses on the exploration of halogen bond by quantum chemical calculations.Noncovalent interactions play a vital role in chemical reactions and physical phenomena.Halogen bond(XB)is a non-covalent interaction similar to hydrogen bond,which is formed between halogen atoms(X=Cl,Br or I)as lewis acid and neutral or negative charged lewis base(such as O,N,S and so on),which attract each other.Intermolecular halogen bond has been widely reported and applied in drug design,molecular recognition,life science,crystal engineering and other areas,but intramolecular halogen bonding is rarely investigated.We found some small molecule structures with typical intramolecular halogen bonds by searching the Cambridge Structural Database(CSD).Then structure optimization and energy calculation of the small compounds have been carried out using density functional theory in quantum chemical calculations to study the influence of different substituent groups and solvents on the characteristics of intramolecular halogen bond.Energy of different conformations(with or without intramolecular halogen bond)has been compared and electron density and Laplacian electron density at the BCP(Bond Critical Point)have been analyzed by AIM(Atom in Molecule)theory to determine the existence of intramolecular halogen bond.Charge transfer in the halogen bonding has been analyzed using NBO(Natural Bond Orbital)theory for the investigation of the strength of halogen bonding that are identified between-1.66~-7.81 kcal/mol in this study.In addition,we calculated the intramolecular halogen bonding under solvation effect based on CPCM(Conductive Polarized Continuum Medium)solvation model to explore the effects of halogen bonding on pKa of small molecules in different solutions,indicating that the relative pKa is-0.73 between the structure of intramolecular halogen bonding of iodine and that without halogen bonding.The influence of halogen bonding on logP of small molecules has been compared by COSMO,which indicates that logP in noctanol and water of the structure with intramolecular halogen bonding is higher than that of the structure without halogen bonding.It provides theoretical guidance of halogen bonding for drug design.The third chapter focuses on the investigation of guanidinium-arginine pairing between ligand and receptor in biological systems.A database survey in this study revealed for the first time that there are 227 counterintuitive like-charge guanidinium pairings(Gdm~+-Arg pairings)between ligands and receptors in the PDB(Protein Data Bank),implying the potential guanidinium-arginine binding between guanidinecontaining drugs and their target proteins.Furthermore,there are 145 guanidinecontaining molecules in the DrugBank,showing the prevalence of guanidinium groups in drugs.It has also been reported that the introduction of guanidinium group forming Gdm~+-Arg pairing improved the potency of the drug by more than 8 fold in a typical case.On the basis of the survey,six ligand-protein complexes with typical Gdm~+-Arg pairings were chosen for QM/MM calculations.The calculations at B97-D/6-311++G(d,p)level revealed that the interaction could be as strong as-1.0~-2.5 kcal/mol in DMSO and water,comparable to common intermolecular interactions.The calculations also unveiled that the Gdm~+-Arg pairing interactions change from repulsive to attractive with the increase of dielectric constant,suggesting that solvents with high dielectric constant have a general stabilization effect on the Gdm~+-Arg pairing.This study suggested that the like-charge guanidinium pairing interaction could be used not only for tuning the physical and chemical properties of drug leads,but also for improving ligand binding affinity.The fourth chapter focuses on the transition state calculation of the mechanism of two synthesis reactions of drugs by density functional theory(DFT)with support from experimental results.In the first reaction,the mechanism of new C-H activation reaction by the catalysis of palladium has been studied.The limitation of activation of only traditional site on β carbonyl group has been broken by developing a new activation mode of forming [4,6]-bicyclic metallacycle intermediate with 1-aminonanthraquinone as a bidentate directing group.Site-selective α oxidation reaction has been successfully applied by this method.The transition state energy difference of important intermediates in different reaction pathways has been obtained by theoretical calculations,which indicates the difficulty of obtaining α or β products and explains the reaction mechanism effectively.In the second reaction,good regioselectivity has been discovered in the synthesis of N-substituted 2-pyridones and the reaction pathways of quaternary ammonium salts with different nucleophiles have been systematically explored by quantum chemistry calculations.The calculated free energy barrier of the reactions revealed the selectivity of the reaction pathways and could be used to predict the result accordingly.The fifth chapter of this thesis focuses on the research of discovery of dihydrofolate reductase(DHFR)inhibitors for tuberculosis.Tuberculosis(TB)is an infectious disease worldwide,causing death approximately every 20 seconds.Current treatment of TB involves the problem of drug-resistance and multi-drug resistance,which is making the situation worse for TB patients.There is an urgent need for developing new drugs for Mycobacterium tuberculosis(Mtb)that is a recognized causative pathogen of TB.Twenty-six low molecular weight compounds were detected from a natural product library by Fourier Transform Mass Spectrometry(FTMS),which bind to ten different TB protein targets in a fragment-based screening.Some of these compounds were found to bind with more than one protein,acting as the connection points in the TB network maps.Molecular docking of proteins and compounds was applied to find the binding site and predict the binding pose for each compound.Distinct binding pose of the compounds that are connection points was fixed in the binding pocket and other compounds were docked into the complex of fixed compound and target protein.Compounds that have the same binding mode in single docking and complex docking with another fixed compound are identified.FTMS was carried out to validate the docking results of those compound pairs.Four pairs of two compounds were found to bind with the protein Mtb DHFR individually and together as well.The docking and experimental results match very well with each other.The sixth chapter is the summary and prospect of the works.