Computational Chemistry Studies On Halogen Bonding And Drug Synthetic Reaction Mechanisms And Design Of B-Raf^V600E Inhibitors

Various noncovalent interactions are involved in the drug-target binding process,which should been studied thoroughly to provide guidance for the discovery and design of active compound.The development of computing resources and computational chemistry methods provide strong support for the simulation of complex chemical reaction,which promotes the in-depth studies of drug synthetic reaction mechanisms.This thesis is main focus on quantum chemistry calculations of halogen bonding interactions and synthetic reaction mechanisms,then,the design of novel B-Raf^V600E inhibitors using fragment-based drug design strategies.The first section is the applications of quantum chemistry in drug design,including the theoretical studies of anion-anion halogen bonding（chapter 2）,noncovalent interactions formed by organofluorine in ligand-protein complex（chapter3）and computation of the reaction mechanisms in medicinal chemistry（chapter 4）.Halogen bonding is the noncovalent interaction between the positively chargedσ-hole of organohalogens and nucleophiles.In reality,both the organohalogen and nucleophile could be deprotonated to form anions,which may lead to the vanishing of theσ-hole and possible repulsion between the two anions.However,our database survey in this study revealed that there are halogen bonding-like interactions between two anions.Quantum mechanics（QM）calculations with small model complexes composed of halobenzoates and propiolate indicated that the anion-anion halogen bonding is unstable in vacuum but attractive in solvents.Impressively,the QM optimized halogen bonding distance between the two anions is shorter than that in a neutral system,indicating a possibly stronger halogen bonding interaction,which is verified by the calculated binding energies.Furthermore,natural bond orbital and quantum theory of atoms in molecule analyses also suggested stronger anion-anion halogen bonding than that of the neutral one.Energy decomposition by symmetry adapted perturbation theory revealed that the strong binding might be attributed to large induction energy.The calculations on 4 protein-ligand complexes from PDB by the QM/MM method demonstrated that the anion-anion halogen bonding could contribute to the ligands’binding affinity up to～3 kcal/mol.Therefore,anion-anion halogen bonding is stable and applicable in reality.Organofluorine is widely used in medicinal chemistry,and there are a lot of fluorinated drugs in the market.However,organofluorine involved noncovalent interactions in ligand-protein binding process are barely studied.We tried to give a substantial and systematic view of the noncovalent interactions involving organofluorine by database surveys and quantum chemistry calculations.The diverse interactions formed between fluorine and other atoms,i.e.,carbon,nitrogen,oxygen and sulfur atoms,are picked out by the geometric restriction.We found non-polar residues are more likely to be around the organofluorine than other polar residues.QM calculations of various small molecules indicated thatσ-hole area on the molecular electrostatic potential of organofluorine is positive while a strong electron-withdrawing group or atom is covalent bonded with fluorine.Nevertheless,the anisotropy in electronic charge distribution around fluorine is not so obvious as other halogen atoms,and the halogen bonding interactions formed by fluorine are similar to halogen bonding formed by negative charged halogen donor to some extent.Fluorine also can form attractive interactions with carbon atom,which should be deemed as van der Waals interactions on account of the geometric and electron density data.The interactions are very weak but appear frequently,which should not be ignored.Then,the systematic studies of organofluorine involved noncovalent interactions should lay an important foundation for the discovery of fluorinated drugs.In chapter 4,we calculated the transition states and reaction mechanisms of two synthetic reaction using density functional theory.In the first part,substituted4-alkoxy-2-oxazolines have been synthesized via the reaction of nitriles with?-hydroxyacetals in mild conditions with up to 99%yield.To provide in-depth information for the reaction mechanism,we performed QM calculations and experimental validations.The reaction is proposed to be initiated by the protonation of the acetals to produce carbocations that are then attacked by nitrogen atom of the nitriles,followed by an intramolecular cyclization reaction to form the4-alkoxy-2-oxazolines.The second part is a novel method of efficient Rh（III）-catalyzed C-H benzoxylation reaction.QM calculations support that different with traditional oxidative addition/reductive elimination pathway,a nucleophilic addition pathway is most likely involved in the current reaction system.In the second section,we utilized fragment-based drug design strategies to discovery B-Raf^V600E inhibitors（chapter 5）.The mutation of B-Raf^V600E is widespread in a variety of human cancers.Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma,demonstrating that B-Raf^V600E600E is an ideal drug target.This study focused on developing novel B-Raf^V600E600E inhibitors as drug leads against various cancers with B-Raf^V600E mutation.Using molecular modeling approaches,200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments.Molecular structures of potential inhibitors of B-Raf^V600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules.The structures with high predicted bioactivity were synthesized,followed by in vitro study to identify potent B-Raf^V600E inhibitors.A highly potent fragment binding to the hinge area of B-Raf^V600E was identified via a docking-based structural splicing approach.Using the fragment,14 novel structures were designed by structural reassembly,two of which were predicted to be as strong as marketed B-Raf^V600E inhibitors.Biological evaluation revealed that compound 1m is a potent B-Raf^V600E inhibitor with an IC₅₀value of 0.05μmol/L,which was lower than that of vemurafenib（0.13μmol/L）.Moreover,the selectivity of 1m against B-Raf^WT was enhanced compared with vemurafenib.In addition,1m exhibits desirable solubility,bioavailability and metabolic stability in in vitro assays.Thus,a highly potent and selective B-Raf^V600E600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.