Shah, KhushbuLin, XinQueener, Sherry F.Cody, VivianPace, JimGangjee, Aleem2019-08-092019-08-092018-05-15Shah, K., Lin, X., Queener, S. F., Cody, V., Pace, J., & Gangjee, A. (2018). 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. Bioorganic & medicinal chemistry, 26(9), 2640–2650. doi:10.1016/j.bmc.2018.04.032https://hdl.handle.net/1805/20328To 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 (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.en-USPublisher PolicyDHFR inhibitorsOpportunistic infectionsPneumocystis pneumoniaPyrrolo[2,3-d]pyrimidineshDHFRpjDHFRArticle