Drug design of new therapeutic agents: molecular docking, molecular dynamics simulation, DFT and POM analyses of new Schiff base ligands and impact of substituents on bioactivity of their potential antifungal pharmacophore site

Abstract

Since Schiff base derivatives have a wide range of biological activities, novel Schiff base derivatives were designed and synthesized in satisfactory yields. ¹H NMR, ¹³C NMR, IR, mass and elemental analysis were used to provide a complete structural characterization of the new synthesized Schiff bases (3–6). The antiproliferative activity properties of compounds were tested against two human cancer cell lines including breast (MDA-MB-231) and colon (DLD-1). The compounds overall did not show high cytotoxic activity against both cancer cell lines compared to the positive control drug cisplatin. The synthesized Schiff base compounds were further screened for their in vitro antimicrobial activities against five bacterial strains (Escherichia coli (ATTC 25922), Salmonella thyphimurium (ATTC 14028), Staphylococcus aureus (ATCC 25923), Bacillus subtilis (ATCC 6633), Bacillus cereus (ATCC 11778)) and two fungal strains (Candida albicans (ATCC 10231) and Candida glabrata (ATCC 90030)) using broth micro dilution techniques. The mode of action for the antimicrobial effect in the experimental part was explored through molecular docking. The stability of target-ligand complexes obtained from the docking were assessed through molecular dynamics simulation. The binding affinity of the compounds toward the target protein were also investigated using MMPBSA. Furthermore, electrochemical properties of some compounds was analyzed by DFT calculations. By using POM theory, it becomes more easy to control the bioactivity of drugs. Here, how the physicochemical properties play a crucial role in the orientation of their bioactivity was demonstrated.

Communicated by Ramaswamy H. Sarma

Keywords:

• Antimicrobial activity
• cytotoxic activity
• DFT
• docking
• molecular dynamics simulation
• pyrimidine
• POM (Petra/Osiris/Molinspiration) analyses
• pharmacophore sites identification
• Schiff bases

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contribution

S.A. designed the study, conducted cytotoxic activity studies and wrote the paper. H.K. synthesized Schiff bases. M.T.M. did the molecular docking, MD simulations and DFT calculations. Z.K. helped to synthesis of molecules. A.C. performed antimicrobial assays. F.A.A. helped to write POM analysis section. H.L. executed the POM calculations T.B.H. designed the bioinformatic POM study and wrote POM analysis section.

Additional information

Funding

SA would like to thank Suleyman Demirel University Research Fund for financial support with project number TSG-2021-8458. Also, we want to thank Erciyes University Research Fund (FBA-2019-8639) for their financial support. Erciyes Üniversitesi;Süleyman Demirel University, Isparta, Turkey.