Quantitative Structure-Activity Relationship Of (2-Methyl-3-Biphenylyl) Methanol (MBPM)Analogs As PD-L1 Inhibitor

Cancer is one of the most serious issues in human life.Blocking the programmed cell death protein 1（PD-1）and programmed death ligand-1（PD-L1）pathway is one of the great innovations in the last few years,but only a few numbers of inhibitors can be able to block it.（2-methyl-3-biphenylyl）methanol（MBPM）derivative is one of them.Firstly,the quantitative structure-activity relationship（QSAR）was established for twenty（2-methyl-3-biphenylyl）methanol（MBPM）derivatives as the programmed death ligand-1（PD-L1）inhibitors.Density functional theory（DFT）at the B3LPY/6-31+G（d,p）level was employed to study the chemical structures and properties of the chosen compounds.Highest occupied molecular orbital energy E_HOMO,lowest unoccupied molecular orbital energy E_LUMO,total energy E_T,dipole moment DM,absolute hardnessη,absolute electronegativityχ,softness S,electrophilicityωand energy gapΔE etc were observed and determined.Principal component analysis（PCA）,multiple linear regression（MLR）and multiple non-linear regression（MNLR）analysis were carried out to establish the QSAR.The proposed quantitative models and interpreted outcomes of the compounds were based on statistical analysis.Statistical results of MLR and MNLR exhibit the coefficient R² was 0.661 and 0.758,respectively.Leave-one-out cross-validation（LOO-CV）,r_m² metric,r_m² test,and“Golbraikh&Tropsha’s criteria”analyses were applied for the validation of MLR and MNLR,which indicate two models are statistically significant and well stable with data variation in the external validation towards PD-L1.The obtained results specify that the MNLR model predicts the bioactivity more accuracy than MLR,and the former may be helpful and supporting for evaluation of the biological activity of PD-L1 inhibitor.Secondly,we designed twenty new halogenated derivatives of MBPM.We used several computational studies to find a potent halogenated analogue of MBPM.DFT method at the B3LYP/Midi X level was used to perform the structure optimization and frequency calculation.The Homo-Lumo gap,hardness,softness,and dipole moment of these new modified compounds were obtained.Further,these molecules were subjected to 3 kinds of different molecular docking analysis with PD-L1（PDB ID 5j89）to study the molecular interaction broadly.Fifty nanoseconds（ns）molecular dynamic（MD）simulation and ensemble-based docking for twenty-nine protein dockings with the five candidates were also performed.MD simulations disclose that the modified compounds are more potent than the unmodified MBMP derivative,where Tyr56,Asp122 and Tyr123 residues making H-bond,and this H-bond can play a significant role in drug-protein interactions.Ensemble-based docking shows that compound 7 shows more exceptional binding affinity to the MBPM in most conformations taken from MD simulation.It is observed thatπ–alkyl interaction with the residues of Ala121,Met 115 and Try123,π-πstacking with the residue of Tyr56 and Alkyl interaction with residue Met 115 may be required for the strong ligand binding.Additionally,pharmacokinetic purpose ADME/T analysis suggests the modified analogs are less toxic than the parent compound.So,halogen-directed inhibitors can be excellent candidates for the treatment of cancer as good binding with PD-L1.Finally,100 synthesized（2-methyl-3-biphenylyl）methanol（MBPM）derivatives or small molecules reported to bind with PD-L1 were calculated by using DFT at the B3LPY/6-31+G（d,p）level.Lipinski’s rule of five（RO5）was used to filter all of the optimized compounds.Filtered compounds were taken to further docking.The Auto Dock-Vina and GOLD docking were employed to find out the interaction and binding affinity of these inhibitors with a cross-section area of PD-L1.The docking simulations were carried out over five top-ranked inhibitors with high binding energies ranging from?12.2 to?12.3 kcal/mol,including M30,M38,M48,M51,and M58.The binding affinity and interaction reveal that M51 could strongly bind with PD-L1.It was found that A:Gln66,A:Tyr56,B:Asp122,and B:Tyr123 amino acids are the most involved in making H-bond.Other amino acids A:Tyr56,A:Met 115,A:Ala121,B:Tyr56,B:Met115 and B:Ala121 are strongly involved for hydrophobic interaction.Additionally,the predicted absorption,distribution,metabolism,excretion,toxicity（ADMET）and the predicted activity spectra for substances（PASS）support that M51 is safer and more reliable than other four candidates.Previous experimental evidence and the computational result show that M51 could be a promising inhibitor for binding with PD-L1 to block PD-1/PD-L1 partway.