Identification of novel selective Mtb‐DHFR inhibitors as antitubercular agents through structure‐based computational techniques

Abstract

Inhibition of dihydrofolate reductase from Mycobacterium tuberculosis-dihydrofolate reductase (Mtb-DHFR) has emerged as a promising approach for the treatment of tuberculosis. To identify novel Mtb-DHFR inhibitors, structure-based virtual screening (SBVS) of the Molecular Diversity Preservation International (MolMall) database was performed using Glide against the Mtb-DHFR and h-DHFR enzymes. On the basis of SBVS, receptor fit, drug-like filters, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, 16 hits were selected and tested for their antitubercular activity against the H 37 R V strain of M. tuberculosis. Five compounds showed promising activity with compounds 11436 and 15275 as the most potent hits with IC 50 values of 0.65 and 12.51 μM, respectively, against the H 37 R V strain of M. tuberculosis. The two compounds were further tested in the Mtb-DHFR and h-DHFR enzymatic assay for selectivity and were found to be three-to eight-fold selective towards Mtb-DHFR over h-DHFR with minimum inhibitory concentration values of 5.50, 73.89 µM and 42.00, 263.00 µM, respectively. In silico simulation studies also supported the stability of the protein-ligand complex formation. The present study demonstrates the successful utilization of in silico SBVS tools for the identification of novel and potential Mtb-DHFR inhibitors and compound 11436 ((2,4-dihydroxyphenyl)(3,4,5-trihydroxyphenyl)methanone) as a potential lead for the development of novel Mtb-DHFR inhibitors. K E Y W O R D S antitubercular agents, MABA assay, MolMall database, Mtb-DHFR inhibitor, structure-based virtual screening

Synthesis of Novel Derivatives of 5,6,7,8-Tetrahydroquinazolines Using α-Aminoamidines and In Silico Screening of Their Biological Activity

“…The ligand occupies a long groove, largely aligned by hydrophobic residues, adjacent to the DHFR binding site, such as Phe31. Ligand 3c was found to be well-suited within the DHFR active site, centered around residues Ile5, Gln28, Phe31, Ile94, and Tyr100, respectively [ 25 , 26 , 27 ]. In addition to several hydrophobic interactions, 3c utilized its sulfonamide head group to interact with the protein through some hydrogen bonds by Gln28 ( Figure 1 , Insert Panel ).…”

Discovery of VEGFR inhibitors through virtual screening and energy assessment

“…427877 compounds were racked up from the US-FDA approved drugs database, US-FDA withdrawn drugs database, may bridge database, MDPI database, and Specs database. [15][16][17] F I G U R E 1 Schematic representation of the workflow.…”

Polyethylene Glycol as a Green Medium for the Microwave‐Assisted Synthesis of Guanamines

“…[16] A variety of guanamines were found to inhibit dihydrofolate reductase (DHFR) with selectivity towards parasitic [17] or Mycobacterium tuberculosis DHFR. [18][19][20] For example, 5 inhibited M. tuberculosis DHFR and also demonstrated a synergistic effect with para-aminosalicylic acid (a drug acting upstream to DHFR in the folate pathway). [20] SM-11 was one of the most promising hits identified in the search for serotonin transporter selective reuptake inhibitors.…”

“…Compound 4 was identified as a dual inhibitor of cancer‐relevant targets, Hsp90 and histone deacetylase 6 [16] . A variety of guanamines were found to inhibit dihydrofolate reductase (DHFR) with selectivity towards parasitic [17] or Mycobacterium tuberculosis DHFR [18–20] . For example, 5 inhibited M. tuberculosis DHFR and also demonstrated a synergistic effect with para ‐aminosalicylic acid (a drug acting upstream to DHFR in the folate pathway) [20] .…”