A Cheminformatic Analysis Of Commercial Compounds And Natural Products

With the development of computational capabilities in such as scales and accuracies,computer-aided drug design(CADD)has played a more important role in drug design,which can tremendously shorten time of pharmaceutical R&D(research and development),and significantly reduce cost of high-throughput screening(HTS)by using virtual screening(VS)from two perspectives,ligand-based drug design(LBDD)and structure/receptor-based drug design(SBDD).As for large purchasable compound databases provided by varieties of vendors,which contain so called commercial compounds in this study,are the indispensable part of sources for VS.And it is important to select optimal datasets used in VS for enhancing success rate of the screening and avoiding wasting of materials in later experimental process.So,analyzing structural features and diversities of compounds from different databases is of great necessity.Besides,this is also a golden time for the re-emergency of natural products drug discovery.All kinds of works casting light on values of natural products emerge in an endless stream,which boosts the using of natural products in new drug discovery pipelines greatly.And structural differences between marine natural products(MNPs)and terrestrial natural products(TNPs)are crucial problems within natural products.Consequently,this dissertation concentrates on conducting some structural based cheminformatics analyses of representative purchasable libraries and natural products.In this study,first,the structural features and scaffold diversity of eleven purchasable screening libraries and Traditional Chinese Medicine compound database(TCMCD)were analyzed and compared.Their scaffold diversity represented by the Murcko frameworks and Level 1 scaffolds was characterized by the scaffold counts and cumulative scaffold frequency plots,and visualized by Tree Maps and SAR Maps.The analysis demonstrates that,based on the standardized subsets with similar molecular weight distributions,Chembridge,ChemicalBlock,Mucle,TCMCD and VitasM are more structurally diverse than the others.Compared with all purchasable screening libraries,TCMCD has the highest structural complexity indeed but more conservative molecular scaffolds.Moreover,we found that some representative scaffolds were important components of drug candidates against different drug targets,such as kinases and G protein-coupled receptors(GPCRs),and therefore the molecules containing pharmacologically important scaffolds found in screening libraries might be potentialinhibitors against the relevant targets.This study may provide valuable perspective on which purchasable compound libraries are better for virtual screening of specific targets.Besides,the important physicochemical properties,structural features and drug-likeness of the two sorts of natural products were analyzed and their differences were discussed from an evolutionary perspective in this study.It shows that,MNPs have lower solubility and are often larger than TNPs.On average,particularly seeing from the aspect of unique fragments and scaffolds,MNPs possess more long chains and large rings,especially eight-to ten-membered rings.More nitrogen atoms,halogens,notably bromines,and less oxygen atoms are found in MNPs,suggesting that MNPs may be synthesized by more diverse biosynthetic pathways than TNPs,and that oxygen concentration on the early earth may influences the metabolic evolution.TNPs have more five-or six-membered rings than MNPs,suggesting that they are more structurally stable.Up to 76.83% Murcko frameworks in the marine compounds is unique when compared with the terrestrial ones.Besides,on average,although drug-likeness evaluation of two kinds of natural products is very near,MNPs(78.06%)are more drug-like than TNPs(76.61%),which can be explained by an evolving point that the older species provide more good hits due to the coevolution between organisms and molecules,it is believed that MNPs may bring researchers engaged in drug discovery to a brighter future considering many TNPs have been developed and tremendous potential of MNPs.Likewise,structures and properties of fragmentations from TNPs mentioned in this study can do some good in future drug discovery process too.