Probing the chemical space regulated by DHFR homologs and pyrimidine-based inhibitors

Ubiquitous Dihydrofolate reductase (DHFR) with an indispensable role in folate metabolism has been a major target for antineoplastic, antimicrobial and antiinflammatory drugs [1]. Despite the clinical effectiveness of current treatments, there is an urgent need for design and development of new drugs due to the resistance which is developing through mutations. One of crucial factors for the design of novel selective inhibitors against pathogen DHFRs, with the least side effect, is to understand factors influencing the ligand binding selectivity profiles among DHFRs. The hybrid scaffold containing pyrimidine ring is well-established as an effective scaffold for DHFR inhibition [2]. Hence, we applied proteochemometrics (PCM) approach to evaluate new pyrimidine-based derivatives as potent inhibitors for DHFR homologs [3]. Z-scales and GRID INdependent Descriptors (GRINDs) in addition to their cross-terms, have been correlated to biological activities through conducting partial least squares (PLS) regression. The final model was validated by several internal/external approaches. All calculated parameters have been in good accordance with acceptance criteria