Validation of the computational simplification of the experimental molecule FR900359

Abstract

Literature indicates that the experimental molecule FR900359 relieves bronchial spasm through G-alpha inhibition. This molecule however has a large molecular weight, and its magnitude precludes its systemic use. This study consequently aimed to use virtual screening and de novo design to identify and generate novel structures with a lower molecular weight based on a modelled optimal conformer of FR900359 capable of modulating the G-alpha subunit. The small molecule inhibitor YM254890 was extracted from its complex with the G-alpha subunit as described in PDB crystallographic deposition 3AH8 giving rise to an apo G-alpha subunit. FR900359 was subsequently docked into its ligand binding pocket, conformational analysis performed, and the optimal conformer of FR900359 identified. Pharmacophores of both these molecules were modelled in LigandScout (Wolber, 2005) and submitted to the online database ZincPharmer® for analogous hit identification with acceptance filters being set such that all recruited hits would conform to the Rule of 3 for lead likeness. This stringent search did not yield any hits. The de novo approach was applied next. Seeds were created from the best FR900359 conformer docked into a modelled G-alpha ligand binding pocket map, based on PDB crystallographic deposition 3AH8. De novo growth was attempted using the GROW and LINK algorithms of LigBuilder. Only 2 Lipinski Rule compliant structures were grown with, however, a ligand binding affinity (pKd 5.1 and 4.93 respectively) that was not high enough to guarantee endogenous molecule displacement in a competitive scenario. The implication of these results is that the FR900359 molecule with a molecular weight of 1001.53 Daltons was not suitable for the identification and design of lower weight G-alpha modulators owing to spatial and steric constraints. This result must also be taken into account in the context of future studies. Specifically, even though molecular weight reduction and structural simplification are sound strategies in the acquisition of oral bioavailability in Lipinski Rule violating molecules which can only be used topically, the success of such attempts is by no means guaranteed.