A Review of Molecular Modelling Studies of Dihydrofolate Reductase Inhibitors Against Opportunistic Microorganisms and Comprehensive Evaluation of New Models

Abstract

Dihydrofolate reductase (DHFR) has been used as a target for antimicrobial drug discovery against a variety of pathogenic microorganisms, including opportunistic microorganisms; Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium complex (ma). In this regard, several DHFR inhibitors are reported against pc and tg and ma. However, selectivity issue of these inhibitors over human DHFR often preclude their development and clinical use. In the first part of this work, various computational approaches including available crystallographic structures, binding affinity prediction, pharmacophore mapping, QSAR, homology modelling used for design of DHFR inhibitors against opportunistic microorganisms are reviewed, to understand specific interactions required for inhibition of microbial DHFR. Secondly, comprehensive molecular modelling techniques were used, to establish structure-chemical-feature-based pharmacophore models for pcDHFR, tgDHFR and mammalian DHFR. The results show that, the information encoded by ligand based approaches like pharmacophore mapping and 3D-QSAR methods are in well agreement with the information coded in the receptor structure. A combination of ligand and structure based approaches provides understanding of ligand-receptor interactions. The study indicated that the value of small alkyl moieties at position 5 of the bicyclic nitrogen containing nucleus along with a bulky group attached at the C-6 via suitable linker could optimize activity, with regard to both potency and selectivity.

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

“…Unfortunately, specific inhibition of parasite DHFR is not possible with pyrimethamine, due to its homology with human DHFR; thus, host toxicity is high. Other inhibitors of DHFR have been extensively studied and documented elsewhere in the literature (31)(32)(33)(34) and include 2,4-diaminopyrido 2,3-dipyrimidines (35), experimental sulfonamides (36), 2,4-diaminopteridines, and triazines. Based on available in vitro data, the most promising of the experimental DHFR inhibitors are the triazines; one of these, compound 14, has an IC 50 of 0.02 M (37).…”

Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

“…The advantages of using computer‐aided drug design (CADD) in modern drug discovery have led to the development of entities with a high probability of success through the clinical phases to attain approval as a new drug . Some of the CADD techniques including quantitative structure‐activity relationships (QSAR), molecular dynamics, molecular docking, homology modeling, pharmacophore modeling, virtual screening, and PCM approach have been successfully involved in the design and development of new inhibitors …”

Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

“…Our research group has been involved in the search of DHFR inhibitors for several pathogens including Mtb . Recently, we have designed 2,4‐diamino‐ s ‐triazines with potential activity against Mtb DHFR .…”