Analysis of Physicochemical Properties for Drugs of Natural Origin

Abstract

The impact of time, therapy area, and route of administration on 13 physicochemical properties calculated for 664 drugs developed from a natural prototype was investigated. The mean values for the majority of properties sampled over five periods from pre-1900 to 2013 were found to change in a statistically significant manner. In contrast, lipophilicity and aromatic ring count remained relatively constant, suggesting that these parameters are the most important for successful prosecution of a natural product drug discovery program if the route of administration is not focused exclusively on oral availability. An examination by therapy area revealed that anti-infective agents had the most differences in physicochemical property profiles compared with other areas, particularly with respect to lipophilicity. However, when this group was removed, the variation between the mean values for lipophilicity and aromatic ring count across the remaining therapy areas was again found not to change in a meaningful manner, further highlighting the importance of these two parameters. The vast majority of drugs with a natural progenitor were formulated for either oral and/or injectable administration. Injectables were, on average, larger and more polar than drugs developed for oral, topical, and inhalation routes.

Discovery and Characterization of a Peptoid with Antifungal Activity against Cryptococcus neoformans

“…These physicochemical properties are comparable to the commercial antifungals and antimicrobial peptides analyzed here. Furthermore, the molecular weight, logD 7.4 , and polar surface area are in line with a large number of natural products used to treat infections, 37 indicating that AEC5 may serve as a good lead for antifungal therapeutic development. Furthermore, the stability of AEC5 in human serum was determined following well established protocols.…”

The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery

“…For example, Lipinski's "Rule of Five" for drug-like molecules can be employed to bias library members towards orally bioavailable leads and/or drugs, while other property combinations can be pursued to facilitate the development of injectables. 7 Indeed, a statistical analysis of drugs derived from a natural progenitor showed that physicochemical properties can vary markedly across different therapy areas. 7 Computational design using physicochemical properties prior to derivative synthesis has been increasingly used to produce more desirable libraries.…”

“…Introduction of lipophilic aliphatic chains at C-6 generally led to an increase in activity, while arylation at C-13 resulted in decreased potency. The most potent analogue, 3, bore a lauroyl group (IC 50 2.91-6.78 µM), which was more active than the NP scaffold 1 (IC 50 Oleanolic acid (6) and maslinic acid (7) are found in high concentrations in olive-pomace oil and can be obtained in large amounts from the solid waste resulting from olive-oil production. 21 Triterpenoids such as 6 and 7 possess a range of medicinal benefits including anti-inflammatory, hepatoprotective, analgesic, anti-microbial, virostatic, anticancer, and anti-HIV activities.…”

Consensus Diversity Plots: a global diversity analysis of chemical libraries

“…This is because each representation has its own advantages and disadvantages: molecular scaffolds are straightforward to interpret but they capture part of the chemical structure, missing the information given by side chains [7]; structural fingerprints usually capture the information of the entire structure but are harder to interpret [8]. Whole molecular properties such as physicochemical properties are easy to interpret and are the basis of several drug- and lead-like empirical rules [9, 10]. However, these properties do not always distinguish the collections e.g., it is not uncommon for different compounds to share very similar property profiles.…”