HIV Inhibitor Activity Prognosis Refined Taking Into Account the Drug Conformation at the Active Center of Enzyme

Abstract

Although the search for new drugs with the desired activity spectrum is among the most important problems in pharmaceutical chemistry, the useful properties of a new drug are usually predicted either intuitively or proceeding from the existing notions about the mechanisms of interaction of this compound with physiologically important biological targets (receptors and active or regulatory centers of enzymes). Verification of such a prognosis is a long and expensive procedure. An alternative approach to establishing quantitative structure – activity relationships (QSARs) is offered by mathematical methods based on the construction of formal models of such relations. Unfortunately, the mathematical hypotheses obtained using such formal methods cannot always be interpreted; the accuracy of these methods is not always sufficient for reliably predicting the activity of new compounds. The most promising way out consists in using a combined approach, whereby a mathematical QSAR model is formulated using additional data on the structure (conformation) of molecules at the active center of an enzyme. Below we describe the application of such a combined approach to establishing QSARs and predicting the activity of some nucleoside inhibitors of reverse transcriptase of type 1 HIV.