Going further than Lipinski's rule in drug design

Abstract

While Lipinski's publication of the Ro5 and subsequent work by other authors has made medicinal chemists more aware of the relationships between physical properties and ADMET, it has hardly been a panacea. Pharmaceutical productivity continues to lag, and the industry is exploring new models to improve its output. If we are to progress, we need to move beyond simple models based on lipophilicity and gain a deeper understanding of molecular interactions.

The application of in silico drug-likeness predictions in pharmaceutical research

“…However, the reported studies have confirmed that the drug-likeness filters/rules based on physicochemical properties are not immobile and universal [19,29,36,37,[51][52][53][54][55][56][57] and they should be used cautiously. For example, our studies showed that Rule-of-Five is not a good predictor to estimate intestinal absorption, and even less reliable than a simple molecular property, topological polar surface area (TPSA) [58,59].…”

Potential of agricultural fungicides for antifungal drug discovery

“…Other simplified rule-based drug-likeness and/or lead-likeness definitions were summarized by, for example, AbadZapatero or Walters. [37,38] Rules based on the Lipinski's approach aimed at improvement of oral bioavailability and redistribution of agrochemicals were adopted quickly, see Table 2. Selected agricultural fungicides (including mode of action and FRAC target site code) potentially interesting for drug design.…”

Identification of 1-Methyl-<i>N</i>-(propan-2-yl)-<i>N</i>-({2-[4-(trifluoromethoxy)phenyl]pyridin-4-yl}methyl)-1<i>H</i>-imidazole-4-carboxamide as a Potent and Orally Available Glycine Transporter 1 Inhibitor

“…17,18) Wager et al at Pfizer have proposed the Central Nervous System Multiparameter Optimization (CNS MPO) as a drug-likeness guideline for the development of drugs acting on the CNS. 19) The CNS MPO score is calculated using six physicochemical parameters: (1) calculated distribution coefficient (c Log P); (2) calculated distribution coefficient at pH 7.4 (c Log D); (3) molecular weight (MW); (4) topological polar surface area (tPSA); (5) number of hydrogen bond donor (HBD); (6) pK a of the most basic center; it has been reported that a higher CNS MPO score may increase of the probability of success.…”