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Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening.

ABSTRACT: Spectrophores are novel descriptors that are calculated from the three-dimensional atomic properties of molecules. In our current implementation, the atomic properties that were used to calculate spectrophores include atomic partial charges, atomic lipophilicity indices, atomic shape deviations and atomic softness properties. This approach can easily be widened to also include additional atomic properties. Our novel methodology finds its roots in the experimental affinity fingerprinting technology developed in the 1990's by Terrapin Technologies. Here we have translated it into a purely virtual approach using artificial affinity cages and a simplified metric to calculate the interaction between these cages and the atomic properties. A typical spectrophore consists of a vector of 48 real numbers. This makes it highly suitable for the calculation of a wide range of similarity measures for use in virtual screening and for the investigation of quantitative structure-activity relationships in combination with advanced statistical approaches such as self-organizing maps, support vector machines and neural networks. In our present report we demonstrate the applicability of our novel methodology for scaffold hopping as well as virtual screening.

SUBMITTER: Gladysz R

PROVIDER: S-EPMC5842169 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening.

Gladysz Rafaela R Dos Santos Fabio Mendes FM Langenaeker Wilfried W Thijs Gert G Augustyns Koen K De Winter Hans H

Journal of cheminformatics 20180307 1

Spectrophores are novel descriptors that are calculated from the three-dimensional atomic properties of molecules. In our current implementation, the atomic properties that were used to calculate spectrophores include atomic partial charges, atomic lipophilicity indices, atomic shape deviations and atomic softness properties. This approach can easily be widened to also include additional atomic properties. Our novel methodology finds its roots in the experimental affinity fingerprinting technolo ...[more]

PMID: 29516311

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Project description:Nontypeable Haemophilus influenzae (NTHi) are clinically important Gram-negative bacteria that are responsible for various human mucosal diseases, including otitis media (OM). Recurrent OM caused by NTHi is common, and infections that recur less than 2 weeks following antimicrobial therapy are largely attributable to the recurrence of the same strain of bacteria. Toxin-antitoxin (TA) modules encoded by bacteria enable rapid responses to environmental stresses and are thought to facilitate growth arrest, persistence, and tolerance to antibiotics. The vapBC-1 locus of NTHi encodes a type II TA system, comprising the ribonuclease toxin VapC1 and its cognate antitoxin VapB1. The activity of VapC1 has been linked to the survival of NTHi during antibiotic treatment both in vivo and ex vivo. Therefore, inhibitors of VapC1 might serve as adjuvants to antibiotics, preventing NTHi from entering growth arrest and surviving; however, none have been reported to date. A truncated VapB1 peptide from a crystal structure of the VapBC-1 complex was used to generate pharmacophore queries to facilitate a scaffold hopping approach for the identification of small-molecule VapC1 inhibitors. The National Center for Advancing Translational Sciences small-molecule library was virtually screened using the shape-based method rapid overlay of chemical structures (ROCS), and the top-ranking hits were docked into the VapB1 binding pocket of VapC1. Two hundred virtual screening hits with the best docking scores were selected and tested in a biochemical VapC1 activity assay, which confirmed eight compounds as VapC1 inhibitors. An additional 60 compounds were selected with structural similarities to the confirmed VapC1 inhibitors, of which 20 inhibited VapC1 activity. Intracellular target engagement of five inhibitors was indicated by the destabilization of VapC1 within bacterial cells from a cellular thermal shift assay; however, no impact on bacterial growth was observed. Thus, this virtual screening and scaffold hopping approach enabled the discovery of VapC1 ribonuclease inhibitors that might serve as starting points for preclinical development.

Project description:BackgroundLeishmaniasis,a broad spectrum of diseases caused by several sister species of protozoa belonging to family trypanosomatidae and genus leishmania , generally affects poorer sections of the populace in third world countries. With the emergence of strains resistant to traditional therapies and the high cost of second line drugs which generally have severe side effects, it becomes imperative to continue the search for alternative drugs to combat the disease. In this work, the leishmanial genomes and the human genome have been compared to identify proteins unique to the parasite and whose structures (or those of close homologues) are available in the Protein Data Bank. Subsequent to the prioritization of these proteins (based on their essentiality, virulence factor etc.), inhibitors have been identified for a subset of these prospective drug targets by means of an exhaustive literature survey. A set of three dimensional protein-ligand complexes have been assembled from the list of leishmanial drug targets by culling structures from the Protein Data Bank or by means of template based homology modeling followed by ligand docking with the GOLD software. Based on these complexes several structure based pharmacophores have been designed and used to search for alternative inhibitors in the ZINC database.ResultThis process led to a list of prospective compounds which could serve as potential antileishmanials. These small molecules were also used to search the Drug Bank to identify prospective lead compounds already in use as approved drugs. Interestingly, paromomycin which is currently being used as an antileishmanial drug spontaneously appeared in the list, probably giving added confidence to the 'scaffold hopping' computational procedures adopted in this work.ConclusionsThe report thus provides the basis to experimentally verify several lead compounds for their predicted antileishmanial activity and includes several useful data bases of prospective drug targets in leishmania, their inhibitors and protein--inhibitor three dimensional complexes.

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Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening.

Publications

Spectrophores as one-dimensional descriptors calculated from three-dimensional atomic properties: applications ranging from scaffold hopping to multi-target virtual screening.

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