Characteristics of known drug space. Natural products, their derivatives and synthetic drugs

Abstract

Known drug space (KDS) was analysed for the occurrence of natural products and their derivatives. A database of 1000 marketed drugs was compiled. It was found that 10% of the drugs on the market are unaltered natural products, 29% are their derivatives (semi-synthetics) and the rest (61%) have a synthetic origin. Of the natural products, and their derivatives, polycyclic drugs were the most abundant at 21% followed by simple drugs (16%) and steroids (15%). In regard to the molecular descriptors the natural products had larger statistical means and standard deviations than their synthetic counterparts. It was found that KDS occupies a larger volume in chemical space with respect to drug-like chemicals, i.e., KDS fully encompasses drug-like chemical space with the parameters of molecular weight ≤ 800 g mol −1, log P ≤ 6.5, hydrogen bond acceptors ≤ 15, hydrogen bond donors ≤ 7, polar surface area ≤ 180 Å 2, and rotatable bonds ≤ 17. Only 13% of the drugs analysed are outside one or more of these parameters. The definition of KDS gives drug designers a larger volume to work in compared to drug-like chemical space. However, the bulk of known drugs are found within the volume of drug-like chemical space.