Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery

Abstract

Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.

Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

“…At the end of the assay, the integrity of the monolayer was verified by measuring the amount of lucifer yellow, a fluorophore, which has passed through the membrane using a plate reader (Wallac EnVision reader, PerkinElmer, Massachusetts) and verified to be <2% of the concentration in the donor chamber (21,22). The integrity of the monolayer was assessed post-drug transport as lucifer yellow may interfere with LC/MS analysis.…”

Strategies for Efficient Lead Structure Discovery from Natural Products

“…During biosynthesis, a continuous mutation is a vital process for the organism's adaptation to changing target receptors related to defense, protection, attraction, and signalling. Firstly, this process enriches the metabolites' structural diversity [22] and, secondly, it optimizes drug-like metabolic traits likely to have favorable pharmacokinetic properties [23,24]. Both may be considered as natural processes of selection, which results in species which are well equipped with a variety of secondary metabolites for survival.…”

“…Furthermore, nature provides several metabolites endowed with the quite uncommon property of interfering with the tubulin cytoskeleton, e.g. colchicines (22), vinblastine (23), vincristine (24), and paclitaxel (25; Taxol A) [34], thus acting as inhibitors of mitosis. The effect of colchicine was already described by Pernice in 1889.…”

“…One should not forget, however, that additional molecular characteristics not reflected by pharmacophore models (physico-chemical, ADME and toxicological properties) must be taken into account when deciding upon which compounds should be further developed [24]. This may also be true for natural products, with physico-chemical properties often not optimal for direct application as drug molecules.…”

Diversity in Medicinal Chemistry Space

“…Many combinatorial libraries such as those arising form MultiComponent Reactions (MCR) [257] and form DiversityOriented Synthesis (DOS) [258][259][260][261][262][263] are targeted at creating natural product-like libraries. DOS was started in the late 1990s and involves the synthesis of chemical libraries containing structurally more complex organic molecules with a range of scaffold and stereo-chemical variations [237,238,264,265].…”