ABSTRACT
Small molecules such as 9,10-dihydrophenanthrene derivatives have remarkable activity toward inhibition of SARS-CoV-2 3CLpro and COVID-19 proliferation, which show a strong correlation between their structures and bioactivity. Therefore, these small compounds could be suitable for clinical pharmaceutical use against COVID-19. The objective of this study was to remodel the structures of 9,10-dihydrophenanthrene derivatives to achieve a powerful biological activity against 3CLpro and favorable pharmacokinetic properties for drug design and discovery. Therefore, by the use of bioinformatics techniques, we developed robust 3D-QSAR models that are capable of describing the structure-activity relationship for 46 molecules based on 9,10-dihydrophenanthrene derivatives using CoMFA/SE (R 2 = 0.97, Q 2 = 0.81, R 2 pred = 0.95, c R 2 p = 0.71) and CoMSIA/SEHDA (R 2 = 0.94, Q 2 = 0.76, R 2 pred = 0.91, c R 2 p = 0.65) techniques. Accordingly, 96 lead compounds were generated based on a template molecule that showed the highest observed activity in vitro (T40, pIC50 = 5.81) and predicted their activities and bioavailability in silico. The rational screening outputs of 3D-QSAR, Molecular docking, ADMET, and MM-GBSA led to the identification of 9 novel modeled molecules as potent noncovalent drugs against SARS-CoV-2-3CLpro. Finally, by molecular dynamics simulations, the stability and structural dynamics of 3CLpro free and complex (PDB code: 6LU7) were discussed in the presence of samples of 9,10-dihydrophenanthrene derivative in an aqueous environment. Overall, the retrosynthesis of the proposed drug compounds in this study and the evaluation of their bioactivity in vitro and in vivo may be interesting for designing and discovering a new drug effective against COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02004-z.