The historical application of molecules of natural origin as starting points for drug discovery has largely been replaced by today's primary hit-seeking strategies of library screening (diversity-based, fragment-based, knowledge-based, virtual) and exploitation of known compounds. Accordingly, the computed natural product (NP) probability score of approved oral drugs has fallen significantly for drugs invented after 1990, when primary in vitro screening at cloned human targets began to be widely adopted. Despite this change, NPs, their derivatives, and synthetic compounds inspired by NPs make up 6%, 28% and 33% respectively of all small molecule drugs approved from 1981 to 2019. This is consistent with the widespread appearance in approved drugs of NP partial structures and fragments. Opportunities for the re-emergence of NPs in drug discovery have been widely heralded. Pseudo-natural products (PNPs) provide a new approach to quantifying the appearance of NP structural elements. PNPs contain low molecular weight NP fragments, selected from a designed library, which are connected in defined ways not currently known to be achievable by biosynthetic pathways. The PNP concept has been validated by their appearance in the literature and by the design of several new classes of biologically active compounds. Thousands of PNPs are available from commercial sources, and a PNP screening library can be readily established. Some 90% of approved drugs have a Tanimoto similarity of >0.5 to their structurally closest human endogenous metabolite, and screening collections were found to be less 'metabolite-like' than drugs. NP-likeness has been proposed to assist drug permeation via transporters, which evolved to facilitate entry of beneficial exogenous natural molecules, helping achieve selective tissue access and therapeutic efficacy. The aim of this work is to seek further support for the existence of 'natural selection' in drug discovery. We employ a highly curated dataset from ChEMBL (version 32) to assess the impact of quantitative NP measures, including the presence of PNPs, in marketed drugs and phase 1-3 clinical compounds in comparison with a background of relevant, target-matched reference compounds.