Index: head/science/rdkit/Makefile
===================================================================
--- head/science/rdkit/Makefile
+++ head/science/rdkit/Makefile
@@ -17,14 +17,15 @@
 		rapidjson>=0:devel/rapidjson
 LIB_DEPENDS=	libboost_system.so:devel/boost-libs
 
-USES=		bison:build cmake eigen:3 python
+USES=		bison:build cmake compiler:c++11-lang eigen:3 python
 USE_GITHUB=	yes
 GH_TUPLE=	schrodinger:maeparser:1.0.0:maeparser/External/CoordGen/maeparser \
 		schrodinger:coordgenlibs:ede3191:coordgenlibs/External/CoordGen/coordgenlibs
 USE_LDCONFIG=	yes
 
 CMAKE_OFF=	RDK_INSTALL_INTREE RDK_USE_FLEXBISON \
-		RDK_INSTALL_STATIC_LIBS RDK_SWIG_STATIC RDK_PGSQL_STATIC
+		RDK_INSTALL_STATIC_LIBS RDK_SWIG_STATIC RDK_PGSQL_STATIC \
+		RDK_OPTIMIZE_NATIVE
 CMAKE_ARGS=	-DFREEBSD_DOCSDIR:PATH=${DOCSDIR} -DCATCH_DIR=${LOCALBASE}
 
 DATADIR=	${PREFIX}/share/RDKit
@@ -45,6 +46,14 @@
 			${PYTHON_PKGNAMEPREFIX}reportlab>0:print/py-reportlab@${PY_FLAVOR}
 
 PORTDOCS=	*
+
+.include <bsd.port.options.mk>
+
+.if ${ARCH} == aarch64 || ${ARCH} == amd64 || ${ARCH:Marm*} || ${ARCH} == i386 || ${ARCH:Mmips*el*} || ${ARCH} == riscv
+PLIST_SUB+=	LITTLE_ENDIAN=""
+.else
+PLIST_SUB+=	LITTLE_ENDIAN="@comment "
+.endif
 
 post-extract:
 	@${MKDIR} ${WRKSRC}/External/rapidjson-1.1.0
Index: head/science/rdkit/pkg-plist
===================================================================
--- head/science/rdkit/pkg-plist
+++ head/science/rdkit/pkg-plist
@@ -295,9 +295,9 @@
 include/rdkit/RDGeneral/types.h
 include/rdkit/RDGeneral/utils.h
 include/rdkit/RDGeneral/versions.h
-include/rdkit/SimDivPickers/DistPicker.h
-include/rdkit/SimDivPickers/HierarchicalClusterPicker.h
-include/rdkit/SimDivPickers/MaxMinPicker.h
+%%LITTLE_ENDIAN%%include/rdkit/SimDivPickers/DistPicker.h
+%%LITTLE_ENDIAN%%include/rdkit/SimDivPickers/HierarchicalClusterPicker.h
+%%LITTLE_ENDIAN%%include/rdkit/SimDivPickers/MaxMinPicker.h
 lib/cmake/rdkit/rdkit-config-version.cmake
 lib/cmake/rdkit/rdkit-config.cmake
 lib/cmake/rdkit/rdkit-targets-%%CMAKE_BUILD_TYPE%%.cmake
@@ -416,9 +416,9 @@
 lib/libRDKitShapeHelpers.so
 lib/libRDKitShapeHelpers.so.1
 lib/libRDKitShapeHelpers.so.1.%%SHLIB_VER%%
-lib/libRDKitSimDivPickers.so
-lib/libRDKitSimDivPickers.so.1
-lib/libRDKitSimDivPickers.so.1.%%SHLIB_VER%%
+%%LITTLE_ENDIAN%%lib/libRDKitSimDivPickers.so
+%%LITTLE_ENDIAN%%lib/libRDKitSimDivPickers.so.1
+%%LITTLE_ENDIAN%%lib/libRDKitSimDivPickers.so.1.%%SHLIB_VER%%
 lib/libRDKitSmilesParse.so
 lib/libRDKitSmilesParse.so.1
 lib/libRDKitSmilesParse.so.1.%%SHLIB_VER%%
@@ -440,9 +440,9 @@
 lib/libRDKitcoordgenlib.so
 lib/libRDKitcoordgenlib.so.1
 lib/libRDKitcoordgenlib.so.1.%%SHLIB_VER%%
-lib/libRDKithc.so
-lib/libRDKithc.so.1
-lib/libRDKithc.so.1.%%SHLIB_VER%%
+%%LITTLE_ENDIAN%%lib/libRDKithc.so
+%%LITTLE_ENDIAN%%lib/libRDKithc.so.1
+%%LITTLE_ENDIAN%%lib/libRDKithc.so.1.%%SHLIB_VER%%
 lib/libRDKitmaeparser.so
 lib/libRDKitmaeparser.so.1
 lib/libRDKitmaeparser.so.1.%%SHLIB_VER%%
@@ -640,7 +640,7 @@
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/Butina.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/ClusterUtils.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/ClusterVis.py
-%%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/Clustering.so
+%%LITTLE_ENDIAN%%%%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/Clustering.so
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/Clusters.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/Murtagh.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/ML/Cluster/Resemblance.py
@@ -724,7 +724,7 @@
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/RDRandom.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/SimDivFilters/SimilarityPickers.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/SimDivFilters/__init__.py
-%%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/SimDivFilters/rdSimDivPickers.so
+%%LITTLE_ENDIAN%%%%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/SimDivFilters/rdSimDivPickers.so
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/TestRunner.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/VLib/Filter.py
 %%PYTHON%%%%PYTHON_SITELIBDIR%%/rdkit/VLib/Node.py