Studies On Molecular InteractionsOligo-Mannose/DC-SIGN, Small Peptide/DNA

Theoretical technique combilned with experimental method has becomepowerful tool in the strudy on interaction between molecules and rational drug design.In this thesis, molecular mechanical and quantum mechanical were used to design theligands or inhibitors of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN);Quantum mechanical and molecular docking technicals were used to study themechanism how Ser-His depeptide can cleave DNA;Neutral network (NN) was usedto precit the stability of oligonucleotide duplexes. On the other hand, small moleculesof monomannose derivatives were synthesized and their interactions with DC-SIGNwere investigated by Ultraviolet spectrum (UV), Circular dichroism (CD) andFluorescence spectrum (FL). All the above theoretical study agreed withexpereimental results very well, and the combined study help us to understand theinsight interaction between molecules much better than single study.1. Based in the complex structure of DC-SIGN and pentasaccaride, a series ofmonomannose derivatives were designed using molecular docking method, and weresynthesized. During the synthesis, a novel method to make activated mannose/altrosebuilding blocks was developed and one crystal structure was characterized by X-ray.Most interestingly, UV, CD and FL study revealed that the designed small moleculesalmost interact with DC-SIGN in the sequence predicted by theoretical study. Thissystematical and original study is very significant for developing novel class ofanti-HIV agents.2. In past decade, one of the most wxciting achievements in our laboratory is thediscovery that small dipeptide (Ser-His) can cleave DNA. In this thesis, moleculardocking studies were performed on DNA model and small peptide complexes, and itis verified that the imidazole group of Histidine play a role to bind with DNA and thehydroxyl group of Serine play a role to cleave phosphodiester bond of DNA bynucleophilic substitution. This study will be helpful for design more active DNAcleavage agents.3. The stability of oligonucleoxide duplexes is a key factor to design antisense,RNAi and other nucleic acid drug system. The present method to predict the stabilityis thermodynamic parameter technique (TP), the disadvantage of this method is that aseries thermodynamic parameters must be determined in different concentration. Inthis thesis, NN technique was developed to predict the stability (Tm), this methodomitted the time consuming measurement of thermodynamic parameters and canpredict the Tm direct from the oligonucleotide sequences. It was proved that the NNmethod is a reliable way comparable with TP method. This method had practicalsignificance.