ABSTRACT
Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information.
Subject(s)
Antibodies, Viral , COVID-19 , Humans , Antibodies, Viral/chemistry , SARS-CoV-2/metabolism , Protein Binding , Amino Acid SequenceABSTRACT
A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 µM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Drug Design , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/metabolism , Antitubercular Agents/pharmacology , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Membrane Transport Proteins/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Mycobacterium tuberculosis/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Protein Conformation , Pyrrolidines/metabolism , Pyrrolidinones/metabolism , Structure-Activity RelationshipABSTRACT
In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Antitubercular Agents/chemical synthesis , Bacterial Proteins/metabolism , Humans , Microbial Sensitivity Tests , Models, Molecular , Mycobacterium tuberculosis/growth & development , Oxidoreductases/metabolism , Pyrrolidines/chemical synthesis , Structure-Activity Relationship , Tuberculosis/drug therapyABSTRACT
We report here the discovery, synthesis and screening results of a series of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione derivatives as a novel class of potent inhibitors of Mycobacterium tuberculosis H37Rv strain as well as the enoyl acyl carrier protein reductase (ENR) InhA. Among them, several compounds displayed good activities against InhA which is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of the mycobacteria cell wall. Furthermore, some exhibited promising activities against M. tuberculosis and multi-drug resistant M. tuberculosis strains.
Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Pyrrolidinones/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Bacterial Proteins/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Kinetics , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/growth & development , Oxidoreductases/metabolism , Pyrrolidinones/chemical synthesis , Pyrrolidinones/chemistry , Structure-Activity RelationshipABSTRACT
In the title compound, C23H18FNO3, the tricyclic 9-fluorenyl system is approximately planar (r.m.s. deviation = 0.0279â Å). The N-C(=O) bond length is comparatively short [1.359â (3)â Å], which is typical for such conjugated systems. The N atom has a planar configuration [sum of bond angles= 359.8°] due to conjugation of its lone pair with the π-system of the carbonyl group. In the crystal, a three-dimensional network is formed through N-Hâ¯O and O-Hâ¯O hydrogen bonds between the amide and carb-oxy-lic acid groups and carbonyl O-atom acceptors.
