Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: how far can they be simplified?

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…However, if the degree of framework overlap is maximized and the size of the combined ligands is minimized, drug‐like ligands can be obtained. Focused or diversity‐based screening may afford a route to smaller and more compact molecules …”

“…3.1 | To design (PROTACs) by exploiting the solvent-exposed region Targeted protein degradation, using heterobifunctional small molecules (PROTACs) to remove protein targets from within cells, has emerged as a novel strategy for drug development, with the opportunity of providing therapeutic interventions not achievable with existing occupancy-based enzyme inhibition approaches. [156][157][158][159][160][161] Small-molecularweight synthetic PROTACs (185)(186)(187)(188)(189) have been used to selectively degrade various specific proteins (Figure 26), including pirin, 162 sirt2, 163 BET protein, 164 androgen receptor, 165 and BRD4 protein. 166 PROTACs consist of a targeting ligand (warhead) for the specific protein to be degraded, an E3 ubiquitin ligase recruitment binder, and a suitable linker connecting the two binders ( Figure 27).…”

“…Focused or diversity-based screening may afford a route to smaller and more compact molecules. 188 The privileged structure is a very important concept in medicinal chemistry. [189][190][191] Interestingly, some privileged (solvent-friendly) moieties, including sulfonyl, sulfonamide, morpholine, piperidine, and piperazine, have been introduced into solvent-exposed regions to improve aqueous solubility, cellular permeability, and metabolic stability.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…This led to the "drug-likeness" concept, where physicochemical descriptors are used to predict how "druggable" a compound is, pioneered by Lipinsky with his "Rule of Five" proposed in 1997 [17]. Since then, diverse algorithms have been advanced to estimate the bioavailability of a compound [18], but tools to predict the ability to cross the blood-brain barrier (BBB) remain scarce. Anticipation of such ability is crucial for any drug candidate, as while some drugs have to cross the BBB to exert their action, others should not, to avoid unwanted effects.…”

Scoring ligand efficiency

“…A high LE preference for small ligands (13,14) fits into the recent trends in pharma that favor small molecular ligands (the so-called slim pharma concept) (20), which have advantageous drug-likeness profiles (21). Therefore, LE performs unexpectedly well if used as guideline filters during the hit and lead optimization (22)(23)(24)(25) despite the uncertainty in its physical meaning (13,14). This uncertainty causes effects that have been interpreted as being unexpected and paradoxical.…”