Combined hormone drugs are the basis for orally administered contraception. However, they are associated with severe side effects that are even more impactful for women in developing countries, where resources are limited. The risk of side effects may be reduced by non-hormonal small molecules which specifically target proteins involved in fertilization. In this study, we present a virtual docking experiment directed to discover molecules that target the crucial fertilization interactions of JUNO (oocyte) and IZUMO1 (sperm). We docked 913,000 molecules to two crystal structures of JUNO and ranked them on the basis of energy-related criteria. Of the 32 tested candidates, two molecules (i.e., Z786028994 and Z1290281203) demonstrated fertilization inhibitory effect in both an in vitro fertilization (IVF) assay in mice and an in vitro penetration of human sperm into hamster oocytes. Despite this clear effect on fertilization, these two molecules did not show JUNO–IZUMO1 interaction blocking activity as assessed by AVidity-based EXtracellular Interaction Screening (AVEXIS). Therefore, further research is required to determine the mechanism of action of these two fertilization inhibitors.
Targeting protein–protein interactions (PPIs)
by small molecule
modulators (iPPIs) is an attractive strategy for drug therapy, and
some iPPIs have already been introduced into the clinic. Blocking
PPIs is however considered to be a more difficult task than inhibiting
enzymes or antagonizing receptor activity. In this paper, we examine
whether it is possible to predict the likelihood of molecules to act
as iPPIs. Using our in-house iterative stochastic elimination (ISE)
algorithm, we constructed two classification models that successfully
distinguish between iPPIs from the iPPI-DB database and decoy molecules
from either the Enamine HTS collection (ISE 1) or the ZINC database
(ISE 2). External test sets of iPPIs taken from the TIMBAL database
and decoys from Enamine HTS or ZINC were screened by the models: the
area under the curve for the receiver operating characteristic curve
was 0.85–0.89, and the Enrichment Factor increased from an
initial 1 to as much as 66 for ISE 1 and 57 for ISE 2. Screening of
the Enamine HTS and ZINC data sets through both models results in
a library of ∼1.3 million molecules that pass either one of
the models. This library is enriched with iPPI candidates that are
structurally different from known iPPIs, and thus, it is useful for
target-specific screenings and should accelerate the discovery of
iPPI drug candidates. The entire library is available in Table S6.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.