Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents

Autor: Khushbu Shah, Vivian Cody, Xin Lin, Aleem Gangjee, Jim Pace, Sherry F. Queener
Rok vydání: 2018
Předmět:
0301 basic medicine
Stereochemistry
030106 microbiology
Clinical Biochemistry
Pharmaceutical Science
Plasma protein binding
Crystallography
X-Ray
Pneumocystis carinii
Biochemistry
Article
03 medical and health sciences
Species Specificity
Catalytic Domain
Drug Discovery
Dihydrofolate reductase
medicine
Humans
Pyrroles
Homology modeling
Amino Acids
Binding site
Molecular Biology
IC50
Enzyme Assays
chemistry.chemical_classification
Molecular Structure
Sequence Homology
Amino Acid
biology
Chemistry
Organic Chemistry
Hydrogen Bonding
Trimethoprim
Anti-Bacterial Agents
Amino acid
Molecular Docking Simulation
Tetrahydrofolate Dehydrogenase
Pyrimidines
Trimetrexate
Drug Design
biology.protein
Folic Acid Antagonists
Molecular Medicine
Hydrophobic and Hydrophilic Interactions
Protein Binding
medicine.drug
Zdroj: Bioorganic & Medicinal Chemistry. 26:2640-2650
ISSN: 0968-0896
DOI: 10.1016/j.bmc.2018.04.032
Popis: To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC(50)) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.
Databáze: OpenAIRE
Externí odkaz: