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

Abstract

Solvent‐exposed regions, or solvent‐filled pockets, within or adjacent to the ligand‐binding sites of drug‐target proteins provide opportunities for substantial modifications of existing small‐molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent‐exposed regions of proteins in drug design and development from the recent medicinal‐chemistry literature.

Druggability modification strategies of the diarylpyrimidine‐type non‐nucleoside reverse transcriptase inhibitors

“…Prodrug strategy is an effective approach in the improvement of druggability 105 . Commonly, a prodrug contains the parent drug with a spacer and a specifier.…”

Discovery of Novel Dihydrothiopyrano[4,3-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles

“…The molecular details of the binding mode between the 3 / 4 and RT indicated that the two protein–solvent interfaces (i.e., the tolerant region I and the entrance channel) provide an underexploited region for the development of novel NNRTIs. In addition, both of them can favorably accommodate various substituents and be involved in the formation of multiple molecule–protein interactions, thus becoming valuable sites for further exploration. , …”

“…In addition, both of them can favorably accommodate various substituents and be involved in the formation of multiple molecule−protein interactions, thus becoming valuable sites for further exploration. 25,26 In the present work, based on the above detailed analysis, a series of novel dihydrothiopyrano [4,3-d]pyrimidine derivatives featuring the piperidin-4-yl-amino moiety or p-cyanoaniline analogues in the right wing were rationally designed via the scaffold hopping and molecular hybridization strategies (Figure 2). Nowadays, the concept of "fraction of sp 3 carbon atoms" (i.e., Fsp 3 , the ratio of the number of carbon atoms with sp 3 hybridization to the total number of carbon atoms) has been proposed to determine the carbon saturation of molecules and characterize the complexity of molecular space structure.…”

Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties

“…1b) indicated that the right benzonitrile moiety pointed to a rather plastic "groove" of NNIBP, known as the solvent-exposed tolerant region I [29]. Solvent-exposed regions could well accommodate diverse polar or hydrophilic substituents, which contribute to establish additional and specific protein-ligand interactions, as well as to elevate physicochemical properties [30]. Thus, the strategy of exploiting solvent-exposed regions has great potential in improving binding affinity, enhancing selectivity and overcoming drug resistance.…”