Future De Novo Drug Design

Abstract

The computer-assisted generation of new chemical entities (NCEs) has matured into solid technology supporting early drug discovery. Both ligand- and receptor-based methods are increasingly used for designing small lead- and druglike molecules with anticipated multi-target activities. Advanced "polypharmacology" prediction tools are essential pillars of these endeavors. In addition, it has been realized that iterative design-synthesis-test cycles facilitate the rapid identification of NCEs with the desired activity profile. Lab-on-a-chip platforms integrating synthesis, analytics and bioactivity determination and controlled by adaptive, chemistry-driven de novo design software will play an important role for future drug discovery.

Molecular structures enumeration and virtual screening in the chemical space with RetroPath2.0

“…RetroPath2.0 can easily be used with source molecules and reaction rules different that those presented in the paper. For instance the workflows provided in Supplementary can be used with the reaction SMARTS rules and fragment libraries (as source compounds) of the DOGS software (inSili.com LLC [4]) developed for de novo drug design, other technique evolving molecules toward specific activities or properties [40, [50][51][52] could also be implemented in RetroPath2.0 provided that one first codes reaction rules in SMARTS format.…”

“…Yet, within their respective application fields, specific rules have been used to discover novel molecules and reaction pathways. Taking experimentally validated examples, the rules associated with the ligand-based de novo design software DOGS (inSili.com LLC) [4] have enabled the production of new chemical entities inhibitors of DAPK3 (death-associated protein kinase 3) [20], metabolic rules for promiscuous enzymes have allowed the discovery of novel metabolites in E. coli [21] and have also been used to engineer metabolic pathways producing 1,4-butanediol [9] and flavonoids [22].…”

“…The enzymatic rules are also used to propose novel molecules completing E. coli metabolic network and for which masses are found in cell lysate mass spectra. 4 All results presented in this paper have been produced making use of the open source workflow RetroPath2.0. RetroPath2.0 and the associated data are provided as Supplementary and can be downloaded at MyExperiment.org.…”

Structure versus function—The impact of computational methods on the discovery of specific GPCR–ligands

“…For an extensive review of different virtual screening methods see Murgueitio et al [26] and Lavecchia et al [27]. A second promising source of novel GPCR modulators is the de novo design of desired compounds which aims at building new chemical entities from scratch [28]. Virtual screening: Molecular docking is the most commonly used computational screening method for the discovery of new GPCR ligands [29].…”

Considerations of Protein Subpockets in Fragment‐Based Drug Design

“…A number of reviews have discussed recent advances in fragment-based drug design and how these tools can be used to improve the lead design process (4,(7)(8)(9)(10)(11)(12)(13)(14). Yet, relatively few evaluations have appeared which address the importance of small localized environments in a proteinbinding site, and how microenvironments ultimately drive ligand binding and observed effects such as drug nonspecificity.…”