Design Of Allosteric Scoring Function And Identification Of Allosteric Signal Pathway

As academic and industry focused on allosteric drugs as the direction of next generation of drug development,works and papers about allosteric site,allosteric co-crystal are increasing.It is main challenge in this area as how to make good use of the experimental data and further design medicinal compounds based on allosteric site,also how to understand allosteric pathway/mechanism based on existing allosteric crystal to provide guidance for allosteric compounds design and optimization.This article will introduce my bioinformatics research work for above challenges by four chapters:Chapter One introduce the concept of allosteric and its development history,including the merits and demerits of allosteric drugs being a new generation of drug design and development direction,also cases of already on market allosteric drugs.These information reveals the reality significance of design algorithms and tools aimed at allosteric issue.Chapter Two introduce the source data required for mathematical modeling which is known as allosteric database(ASD),and the work about this database V3.0 updated version published in 2016.Allosteric database is no longer merely focused on collection of allosteric proteins and allosteric compounds since its inception,it has become an integrated platform for allosteric phenomenon research from single protein,protein family,signal pathways and other multiple levels.This platform has provided every discipline or every direction allosteric researchers with precious data information.Chapter Three is the research on design of allosteric scoring function.Scoring function is the core part of drug design software and is responsible for screening the potential leading compounds from vast amounts of compounds.As the allosteric interaction has its own special features,general scoring function can no longer meet the requirements for screening allosteric compounds.So,it is of significance to design a scoring function featured at allosteric.This chapter will firstly summarize the development status of scoring function and present out the possibility and necessity of design a scoring function featured at allosteric.Secondly this chapter will introduce the detailed design and release of allosteric scoring function “Alloscore”,also its follow-up expectation as to use deep learning model to design another allosteric scoring function.Chapter Four focus on research of allosteric signal pathway/mechanism.It requires a deep understanding about how allosteric signals are occurred and transferred on targeted proteins for allosteric drug design and optimization.So,Identification of allosteric signal pathway has become a hotspot these years.This chapter firstly introduces various methods and their principles for allosteric pathway prediction at the moment,and then emphasis the community analysis method based on protein dynamic network,also provides a specific case study of the allosteric signal pathway for PTP1 B.