COMPUTATIONAL MODELING OF PHOSPHODIESTERASE 3 INHIBITORS

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Study on the cyclization of 6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine: microwave versus thermal preparation of pyrido[4,3-d]pyrimidines

Publication . Cikotiene, Inga; Kairys, Visvaldas; Buksnaitiene, Rita; Morkunas, Marius; Rudys, Simonas; Brukstus, Algirdas; Fernandes, Miguel X.

Thermal and microwave initiated cyclization of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbalde hydes with tert-butylamine has been studied. A novel high-yielding preparation of 2,4-disubstituted 7- arylpyrido[4,3-d]pyrimidines has been developed. The intermediate compounds were isolated and possible mechanism of the reactions is discussed.

2009Journal article

Open access

Toward the design of mutation‐resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis

Publication . Kairys, Visvaldas; Gilson, Michael K.; Lather, Viney; Schiffer, Celia A.; Fernandes, Miguel X.

Previous studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study tests its applicability to several other thera peutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuramini dase. For the targets where many (‡6) mutation data are available to compute the average mutation sen sitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate enve lope Vout, is found to correlate with average muta tion sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold for the other targets, if more extensive muta tion data sets were available. It is concluded that the substrate envelope concept offers a promising and easily implemented computational tool for the design of drugs that will tend to resist muta tions. Software implementing these calculations is provided with the ’Supporting Information’.

2009Journal article

Open access