Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens

Seema Bag, Nilesh R. Tawari, Mariam S. Degani, Sherry Queener

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The present work deals with design, synthesis and biological evaluation of novel, diverse compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms; Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 14 structurally diverse compounds were designed with varying key pharmacophoric features of DHFR inhibitors, bulky distal substitutions and different bridges joining the distal part and 2,4-diaminopyrimidine nucleus. The designed compounds were synthesized and evaluated in enzyme assay against pc, tg and ma DHFR. The rat liver (rl) DHFR was used as mammalian standard. As the next logical step of the project, flexible molecular docking studies were carried out to predict the binding modes of these compounds in pcDHFR active site and the obtained docked poses were post processed using MM-GBSA protocol for prediction of relative binding affinity. The predicted binding modes were able to rationalize the experimental results in most cases. Of particular interest, both the docking scores and MM-GBSA predicted ΔGbind were able to distinguish between the active and low active compounds. Furthermore, good correlation coefficient of 0.797 was obtained between the IC50 values and MM-GBSA predicted ΔGbind. Taken together, the current work provides not only a novel scaffold for further optimization of DHFR inhibitors but also an understanding of the specific interactions of inhibitors with DHFR and structural modifications that improve selectivity.

Original languageEnglish
Pages (from-to)3187-3197
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number9
DOIs
StatePublished - May 1 2010

Fingerprint

Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Pathogens
Pneumocystis carinii
Mycobacterium avium
Toxoplasma
Scaffolds
Joining
Microorganisms
Liver
Rats
Assays
Enzyme Assays
Substitution reactions
Inhibitory Concentration 50
Catalytic Domain
Enzymes

Keywords

  • 2,4-Diaminopyrimidine
  • Dihydrofolate reductase
  • Docking
  • MM-GBSA

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens. / Bag, Seema; Tawari, Nilesh R.; Degani, Mariam S.; Queener, Sherry.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 9, 01.05.2010, p. 3187-3197.

Research output: Contribution to journalArticle

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