TY - JOUR
T1 - Synthesis and inverse virtual screening of new bi-cyclic structures towards cancer-relevant cellular targets
AU - Crocetti, Letizia
AU - Floresta, Giuseppe
AU - Nazir, Shabnam
AU - Vergelli, Claudia
AU - Bhogal, Amrit
AU - Biancalani, Claudio
AU - Cesari, Nicoletta
AU - Giovannoni, Maria Paola
AU - Cilibrizzi, Agostino
N1 - Funding Information:
S.N. was funded by the Post-Doc Fellowships Programme (3-1/PDFP/HEC/2020/856), Higher Education Commission, Pakistan. G.F. is currently a Marie Skłodowska-Curie fellow funded by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 893784.
Funding Information:
Andrew Beavil (King?s College London) is gratefully acknowledged for providing software resources via King?s Virtual Desktop.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6
Y1 - 2022/6
N2 - We report here synthetic approaches to access new classes of small molecules based on three heterocyclic scaffolds, i.e. 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione, 1,8-naphthyridin-4(1H)-one and 4H-pyrido[1,2-a]pyrimidin-4-one. The bi-cyclic structure 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione is a new heterocycle, described here for the first time. In silico methodologies of inverse virtual screening have been used to preliminary analyse the molecules, in order to explore their potential as hits for chemical biology investigations. Our computational study has been conducted with 43 synthetically accessible small molecules towards 31 cellular proteins involved in cancer pathogenesis. Binding energies were quantified using molecular docking calculations, allowing to define the relative affinities of the ligands for the cellular targets. Through this methodology, 16 proteins displayed effective interactions with distinct small molecules within the matrix. In addition, 23 ligands have demonstrated high affinity for at least one cellular protein, using as reference the co-crystallised ligand in the X-ray structure. The evaluation of ADME and drug score for selected hits also highlights that these new molecular series can serve as sources of lead candidates for further structure optimisation and biological studies.
AB - We report here synthetic approaches to access new classes of small molecules based on three heterocyclic scaffolds, i.e. 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione, 1,8-naphthyridin-4(1H)-one and 4H-pyrido[1,2-a]pyrimidin-4-one. The bi-cyclic structure 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione is a new heterocycle, described here for the first time. In silico methodologies of inverse virtual screening have been used to preliminary analyse the molecules, in order to explore their potential as hits for chemical biology investigations. Our computational study has been conducted with 43 synthetically accessible small molecules towards 31 cellular proteins involved in cancer pathogenesis. Binding energies were quantified using molecular docking calculations, allowing to define the relative affinities of the ligands for the cellular targets. Through this methodology, 16 proteins displayed effective interactions with distinct small molecules within the matrix. In addition, 23 ligands have demonstrated high affinity for at least one cellular protein, using as reference the co-crystallised ligand in the X-ray structure. The evaluation of ADME and drug score for selected hits also highlights that these new molecular series can serve as sources of lead candidates for further structure optimisation and biological studies.
KW - ADME assessment
KW - Bi-cyclic scaffold
KW - Heterocycles
KW - Inverse virtual screening
KW - Scaffold diversity
UR - http://www.scopus.com/inward/record.url?scp=85124730878&partnerID=8YFLogxK
U2 - 10.1007/s11224-022-01889-0
DO - 10.1007/s11224-022-01889-0
M3 - Article
AN - SCOPUS:85124730878
SN - 1040-0400
VL - 33
SP - 769
EP - 793
JO - STRUCTURAL CHEMISTRY
JF - STRUCTURAL CHEMISTRY
IS - 3
ER -
