Enamine Ltd.: The Science and Business of Organic Chemistry and Beyond

Grygorenko, Oleksandr O.

doi:10.1002/ejoc.202101210

Cited by 28 publications

(22 citation statements)

References 15 publications

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“…The top two performing 3D models, one dedicated to agonists and one to antagonists’ detection, were selected in each iteration and employed for virtual screening (VS). Specifically, two cycles of structure-based and mixed structure and ligand based screening of a multi-million compounds library [30] allowed the identification of 3 antagonists and 6 agonists, a remarkable result considering the difficulties in finding TAS2Rs antagonist and the low number (n=29) of computationally predicted compounds that were experimentally tested. In addition, the RVS performances of the AlphaFold model [31] and of a homology model based on the TAS2R46 CryoEM structure [32] (both not available at the beginning of this study) were also evaluated.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

Fierro

Peri

Hübner

et al. 2022

Preprint

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The human GPCR family comprises circa 800 members, activated by hundreds of thousands of compounds. Bitter taste receptors, TAS2Rs, constitute a large and distinct subfamily, expressed orally and extra-orally and involved in physiological and pathological conditions. TAS2R14 is the most promiscuous member, with over 150 agonists and 3 antagonists known prior to this study. Due to the scarcity of TAS2R14 inhibitors and to the importance of chemical probes for exploring TAS2R14 functions, we aimed to discover new ligands for TAS2R14, with emphasis on antagonists. To cope with the lack of experimental structure of the receptor, we used a mixed experimental/computational methodology which iteratively improved the performance of the predicted structure. The increasing number of active compounds, obtained through experimental screening of FDA-approved drug library, and through chemical synthesis of flufenamic acid derivatives, enabled the refinement of the binding pocket, which in turn improved the structure-based virtual screening reliability. This mixed approach led to the identification of 207 new agonists and 10 new antagonists of TAS2R14, illustrating the untapped potential of rigorous medicinal chemistry for TAS2Rs. The iterative framework suggested residues involved in the activation process, is suitable for expanding bitter and bitter-masking chemical space, and is applicable to other promiscuous GPCRs lacking experimental structures.

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Section: Introductionmentioning

confidence: 99%

Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

Fierro

Peri

Hübner

et al. 2022

Preprint

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“…d) Fragment library screening: Fragments are small molecular weight compounds with the ability to bind to different parts of target and cover a large chemical space. Enamine golden library (shared by José A. Marquez group at European Molecular Biology Laboratory (EMBL) Grenoble) [23] with 1204 active fragments was screened against Mtb-DapA protein (Figure 3c). These were obtained in SMILES format, which were converted into 3D structure files using the open-source cheminformatics tool RDKit [24].…”

Section: Ligand Datasetmentioning

confidence: 99%

Screening and Identification of Novel Small Molecule Inhibitors against Mycobacterium tuberculosis Dihydrodipicolinate Synthase Enzyme using In Silico and In Vitro Methods

Bhargav¹,

Chaurasia²,

Ivanisenko³

et al. 2022

Preprint

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Emergence of multi drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to TB control as the available treatment options are less effective in these cases. Therefore, new strategies are required for identification of new drugs and drug targets. The M. tuberculosis dihydrodipicolinate synthase is a putative drug target with no potent inhibitor. Here in this study, we have used a comprehensive computational approach to identify small molecule inhibitors and validated them in vitro. As similar structures tend to have similar functions, therefore 3 approaches, namely, (a) known inhibitor-based approach, (b) substrate analogues, (c) product analogues were used for compound screening from various chemical libraries. The fourth approach we have taken is fragment library screening.In vitro studies revealed that β-hydroxypyruvic acid tartronic acid are inhibitors of Mtb-rDapA with maximum inhibition 48% and 51% at 500µM concentrations respectively. We have also observed that β-hydroxypyruvic acid is a time dependent inhibitor of Mtb-rDapA. Further, thermal shift assays showed that β-hydroxypyruvic acid interacts with Mtb-rDapA and the thermal stability of Mtb-rDapA shifted by 3˚C. Among the product analogues of Mtb-DapA, dipicolinic acid showed to bind to Mtb-rDapB shifting thermal stability of Mtb-rDapB by 0.5˚C in binding. Additionally, we have designed a new approach by combining substrate and product analogues to achieve better inhibitions. In vitro assays validated that this combination approach increased maximum inhibition up to 100%. We envision that these compounds would serve as potent leads for tuberculosis drug discovery.

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“…For example, Enamine Ltd has performed foundational work in this area by providing diverse building blocks and establishing manual on-demand synthesis of molecules from a library of 2.9 x 10 10 members. 14,15 Significant steps towards the fully automated synthesis of virtual screening hits have been achieved by Eli Lilly and Strateos with Idea2Data. 16 This infrastructure unites the Proximal Lilly Collection virtual library with their automated synthesis laboratory.…”

Section: Introductionmentioning

confidence: 99%

A vending machine for drug-like molecules – automated synthesis of virtual screening hits

McMillan

Nichols

et al. 2022

Chem. Sci.

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Enamine Ltd.: The Science and Business of Organic Chemistry and Beyond

Cited by 28 publications

References 15 publications

Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

Screening and Identification of Novel Small Molecule Inhibitors against <em>Mycobacterium tuberculosis</em> Dihydrodipicolinate Synthase Enzyme using <em>In Silico</em> and <em>In Vitro</em> Methods

A vending machine for drug-like molecules – automated synthesis of virtual screening hits

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