Construction And Development Of Hybrid Molecule Database For Drug Discovery

With the development of social and economic and the intensification of aging population,public health issues are getting more attention.However,the existing drugs are insufficient for the treatment of complex diseases.Therefore,there is a need to discover and develop new drugs to support human health.In recent years,traditional drug development has encountered bottlenecks including two main problems:(1)economic problems,such that the number of new molecular entities approved to market each year has shown little or no increase in successful projects,despite an increasing commitment of resources;(2)druggability,the majority of failures of drug development programs are due to the lack of efficacy of therapeutic hypothesis,with unexpected clinical side effects and tolerability being crucial issues,resulting in huge losses for pharmaceutical companies.In order to facilitate the development of new drugs,the concept of hybrid molecule drugs is proposed,which attracts more researchers worldwide.Hybrid molecule drugs are defined as a single molecular entity that are splicing or fusion of two or more bioactive molecules or pharmacophore fragments of bioactive molecules.Hybrids are designed primarily(1)to obtain better affinity and efficacy;(2)to interact with two or multiple targets;(3)to generate new biological or pharmacological effects;(4)to improve properties of precursor molecule,such as selectivity,pharmacokinetics,etc.;(5)to reduce undesirable side effects and to decrease in drug-drug interactions;(6)to reduce emergence of drug resistance;(7)to reduce the cost in drug research & development(R&D).Obviously,there are three major advantages for designing hybrid molecules in drug development campaigns.For one thing,compared with the High Throughput Screening(HTS)method,the process of design hybrid molecules is more reasonable,which,may reduce drug R&D costs.For another,the one goal of designing hybrid molecules is to interact with multiple targets,which may solve the emergence of drug resistance for the drug with single target that shows poor efficacy for the treatment of complex diseases.Last but not least,there is no need to worry about drug-drug interactions and patient compliance issues with respect to combination medications.In view of the above advantages of hybrid molecules,the designing and discovery of hybrid molecules as new drugs has attracted more pharmaceutical companies and academics.The increasing number of hybrid molecules are designed and reported in scientific literatures to cure human diseases,such as cancer,neurodegenerative diseases,malaria,AIDS,and inflammation.However,the data on hybrid molecules are scattered in various journal and relevant databases,which is unfavorable to the data collection and data-based knowledge translation for researchers involved in the field.Therefore,to boost the design and discovery of new hybrid drugs,it is essential to properly collect and annotate experimental data about the known hybrid molecules.To cater to this need,we have developed HybridolMDB,a hand-curated database dedicated to hybrid molecules for chemical biology and drug discovery.It contains the structure,manual-annotated design protocol,the pharmacological data,some physicochemical and drug-like and ADMET characteristics and the profile of targets of known hybrid molecules.HybridMolDB is fully searchable supporting extensive text,sequence,chemical structure and relational query searches.Many data fields in HybridMolDB are hyperlinked to external databases such as ChEMBL,PubMed,DrugBank,Uniprot and PDB.HybridMolDB is freely accessible at http://www.rcidm.org /HybridMolDB/index.php.This paper mainly includes the following chapters:The first chapter mainly introduces the current situation of R&D of new drugs and hybrid molecules,and our research project hypothesis and purpose.The second chapter mainly introduces the information collection,collation and annotation of hybrid molecules and the calculation and analysis of the related properties of hybrid molecules.The third chapter mainly introduces the web-based hybrid molecule database online platform development,function realization and platform exhibition.The fourth chapter mainly analyzes and forecasts on the established HybridMolDB.