Relation between the Molecular Electrostatic Potential and activity of some FF-MAS related sterol compounds

Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta (8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3 beta -OH oxygen atom to the activity of the molecules. (C) 2001 Elsevier Science Ltd. All rights reserved.