Identification of novel inhibitors for mycobacterial polyketide synthase 13 via in silico drug screening assisted by the parallel compound screening with genetic algorithm-based programs

Taira, Junichi; Murakami, Kahori; Monobe, Kohei; Kuriki, Kohei; Fujita, Miu; Ochi, Yosuke; Sakamoto, Hiroshi; Aoki, Shunsuke

doi:10.1038/s41429-022-00549-z

Cited by 8 publications

(7 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RFP was used as a positive control, and DMSO (0.3%) as a negative control. M. smegmatis was incubated in a 96-well plate at 37 °C, 240 rpm, for 24 h. The absorbance of the culture medium was measured at 595 nm using a microplate reader (Bio-Rad Laboratories Inc., Hercules, CA, USA) [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Antimicrobial Compounds Targeting Mycobacterium tuberculosis S-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening

Ito,

Monobe,

Okubo

et al. 2024

Molecules

Self Cite

View full text Add to dashboard Cite

The emergence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (M. tuberculosis) has become a major medical problem. S-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identification of novel anti-TB drugs. Dual hierarchical in silico Structure-Based Drug Screening was performed using a 3D compound structure library (with over 150 thousand synthetic chemicals) to identify compounds that bind to MtSAHH’s active site. In vitro experiments were conducted to verify whether the nine compounds selected as new drug candidates exhibited growth-inhibitory effects against mycobacteria. Eight of the nine compounds that were predicted by dual hierarchical screening showed growth-inhibitory effects against Mycobacterium smegmatis (M. smegmatis), a model organism for M. tuberculosis. Compound 7 showed the strongest antibacterial activity, with an IC50 value of 30.2 µM. Compound 7 did not inhibit the growth of Gram-negative bacteria or exert toxic effects on human cells. Molecular dynamics simulations of 40 ns using the MtSAHH–Compound 7 complex structure suggested that Compound 7 interacts stably with the MtSAHH active site. These in silico and in vitro results suggested that Compound 7 is a promising lead compound for the development of new anti-TB drugs.

show abstract

Section: Methodsmentioning

confidence: 99%

Identification of Novel Antimicrobial Compounds Targeting Mycobacterium tuberculosis S-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening

Ito,

Monobe,

Okubo

et al. 2024

Molecules

Self Cite

View full text Add to dashboard Cite

show abstract

“…Yet, even though Pks13 inhibitors have not been clinically studied or licenced, the target is druggable because it is known to be crucial for bacterial survival that was found in in‐vitro studies [36] . In this study, isoniazid drug and PDB co‐crystallised ligand are utilized as references to compare the outcomes of in‐silico results [37] . Isoniazid is the oldest synthetic antitubercular medication, used first line therapy for active infection, which inhibits mycolic acid production by inactivating the InhA protein [37] …”

Section: Methodsmentioning

confidence: 99%

“…[36] In this study, isoniazid drug and PDB co-crystallised ligand are utilized as references to compare the outcomes of insilico results. [37] Isoniazid is the oldest synthetic antitubercular medication, used first line therapy for active infection, which inhibits mycolic acid production by inactivating the InhA protein. [37] Thioesterase domain (PDB ID: 5V3Y) was downloaded from the Protein data bank (PDB).…”

Section: Molecular Dockingmentioning

confidence: 99%

“…[37] Isoniazid is the oldest synthetic antitubercular medication, used first line therapy for active infection, which inhibits mycolic acid production by inactivating the InhA protein. [37] Thioesterase domain (PDB ID: 5V3Y) was downloaded from the Protein data bank (PDB). The structure was solved by the crystallography technique using the X-ray diffraction method with a resolution of 1.98 Å and 'R-Value free' of 0.239.…”

Section: Molecular Dockingmentioning

confidence: 99%

See 1 more Smart Citation

Identification of Potent Antitubercular Secondary Metabolites from Kigelia africana: An In‐Silico Investigation

Darra Wadhwani,

Nunia,

Joshi

et al. 2023

ChemistrySelect

View full text Add to dashboard Cite

Ethyl‐acetate extract of heartwood of Kigelia africana Lam. affords tecomaquinone‐I (1), lapachol (2), dehydro‐α‐lapachone (3), cluytyl ferulate (4), kigelinone (5), D‐sesamin (6), paulownin (7), wodeshiol (8) and cycloolivil (9). Isolation of cycloolivil from this plant is being reported for the first time. The structures of these compounds were elucidated by advanced spectroscopic methods (1H, 13C NMR, IR & Mass spectrometry). Structure of cycloolivil (9) was confirmed by X‐ray crystallographic analysis. In order to study the anti‐tubercular activity and to develop new drugs from natural sources, molecular docking studies of isolated phytochemicals were performed for potential inhibitory action towards Type I polyketide synthase 13 (Pks13). For this purpose, isoniazid, and a co‐crystallized PDB ligand were used as reference drug. Tecomaquinone‐I exhibited best docking score (−12.4 kcal/mol) among all the tested compounds. Molecular simulation and QSAR study of tecomaquinone‐I favoured docking results. Hence, the present study suggests that tecomaquinone‐I exhibits potent anti‐tubercular activity.

show abstract

“…However, further development of these benzofuran inhibitors was impeded by their associated hERG toxicity . This work fueled a search for novel chemotypes that better target this critical enzyme. − In addition, an inhibitor series based on a thiophene core with potent activity against mycobacteria was found to target the N-terminal acyl carrier protein domain of Pks13 enzyme. − A screening campaign on Pks13-TE resulted in the discovery of an oxadiazole series with potent antimycobacterial activity, but the PK properties of these molecules proved to be insufficient for in vivo evaluation . Despite efforts by multiple laboratories, no new progressable lead has been reported to date.…”

mentioning

confidence: 99%

Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening

Krieger,

Yalamanchili,

Dickson

et al. 2024

ACS Infect. Dis.

View full text Add to dashboard Cite

DNA-encoded chemical library (DEL) technology provides a time-and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

show abstract

Identification of novel inhibitors for mycobacterial polyketide synthase 13 via in silico drug screening assisted by the parallel compound screening with genetic algorithm-based programs

Cited by 8 publications

References 32 publications

Identification of Novel Antimicrobial Compounds Targeting Mycobacterium tuberculosis S-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening

Identification of Novel Antimicrobial Compounds Targeting Mycobacterium tuberculosis S-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening

Identification of Potent Antitubercular Secondary Metabolites from Kigelia africana: An In‐Silico Investigation

Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening

Contact Info

Product

Resources

About