Steering drug discovery efforts away from the flatland

Does high-throughput synthetic practices have failed the drug discovery efforts by steering them toward greater unsaturation leading to more flat aromatic compounds those may not be better complement to the target proteins? Yes at least that’s what Frank Lovering and others are suggesting. In a recent article published in Journal of Medicinal Chemistry Lovering et. al highlight lack of molecular complexity as key limitation of high-throughput parallel synthesis driven drug discovery efforts. In last 10 years due to ease of coupling reactions of flat aromatic moieties high-throughput parallel synthesis efforts have become quite popular contributing a lot to drug discovery efforts but they have also biased efforts at the bench side. By analyzing more than two million compounds retrieved from the GVK BIO database, authors suggest that the the molecular complexity and the presence of chiral centers are key determinants of success in the transition from discovery, through clinical testing, to approved drugs which means that current discovery efforts need to be directed towards diversity-oriented synthesis to produce architecturally complex candidate drug molecules. Molecules with higher complexity and the presence of stereo centers are more likely to succeed in these transitions. The authors chose two simple and interpretable measures of the molecular complexity: (i) carbon bond saturation as defined by fraction sp³ (Fsp³) where Fsp³ = (number of sp³ hybridized carbons/total carbon count) and (ii) existence of chiral centers. Use of saturation as a key descriptor for complexity means increase in complexity without increasing molecular weight significantly. Study also shows that saturation correlates well with solubility. Both molecular weight and solubility are key factor for drug-likeness noted in the Lipinski’s “Rule of 5″. Current study addresses the role of molecular complexity and its connection to “Rule of 5″. Findings will help to design molecules quite similar to natural products with better bioactive by exploring the complex areas of chemical space.