Studies On The Nature Of Drugs: Statistics And Analysis Of Key Physical And Chemical Properties And Structure Of Drugs

The discovery of small molecule drug is complex and difficult. The traditional small molecular drug development process usually preferentially considered the efficacy of molecules, then assessed their druggability, which often led to higher failure rates and development costs. Among the reasons of the drug development failures, the inappropriate pharmacokinetics ranked the first. Because marketed drugs have passed the strict pre-clinical and clinical studies, there is no doubt that these drugs have good drug-likeness. If the common characteristic of the key physicochemical and structural properties of the global small molecular drugs could be summarized as a "gold criterion" to guide the selection, design and optimization of lead compounds and drug candidates in the early stages of preclinical research, it will not only increase the success rate of drug development, but also eliminate those poor drug-like compounds ahead and avoid more research and development expenses. Therefore, the studies of the key physicochemical and structural properties of small molecular drugs have significant theoretical and practical value.Based to these reasons above, this paper carried out a comprehensive and systematic analysis on the key physicochemical and structural properties of all global small molecular chemical drugs before the year 2007 (the total number is 6891, see attached chart). First, through various databases we searched the data of the key physicochemical properties of these drugs, including MP, LogP, pKa, MW, functional groups, number of aromatic ring/non-aromatic ring, the ration of non-hydrocarbon atoms and non-hydrogen atoms (R value). Then we analyzed the physicochemical properties of these drugs, summarized some drug-like criteria, that was the common characteristics of most drugs (eighty percent or ninety percent). Moreover, in order to explore the physicochemical property similarities and differences of drugs with various indications or routes of administration, we divided the whole database into five sub-sets, including oral drugs, CNS drugs, anti-cancer drugs, anti-infective drugs, and cardiovascular drugs.Finally we concluded some drug-like criteria of different physicochemical properties as the new drug-like criteria used to guide the design and optimization of organic small molecular lead compounds, improve the success rate of pre-clinical candidates development.The criteria are as follows:● The MP of candidate drug should be less than 250℃ (preferred for 100℃< MP< 200℃). CNS candidate drug with MP less than 200℃ possess better drug-like properties and have a larger chance to be developed into approved drugs.● The pKa of candidate drug should not be in the range of 5-6, which is "pKa trap".● The LogP of candidate drug should be in the range of 0-6 (preferred for the range of 0-5). In this range, the LogP of anti-infective drug should be smaller, while the LogP of cardiovascular drug should be larger.● The MW of drug with good drug-like property should be commonly less than 500, but not necessary. The MW of CNS drug with good drug-like property should be less than 400, while the MW of anti-cancer drug with good drug-like properties could be allowed to be up to 650.● If a candidate drug contains aromatic rings or non-aromatic rings, the optimum values of the ring number are 2 and 1, respectively.● The R value of candidate drug should be in the range of 0.05-0.50 (preferred for the range of 0.10-0.40). In this range, the R value of CNS drug should be smaller, while the R value of anti-infective drug should be larger.● The candidate drug should preferentially choose the functional groups like OH, COOR and COOH (the best substituent:OH), and rarely choose functional groups like CONHOH, SH, CHO and SO3H (the worst substituent:SH). F substituent is beneficial to CNS drug, while NH2 substituent is beneficial to anti-infective drug and anti-cancer drug.