The use of computer-aided drug design in small molecule drug discovery

Abstract

Drug discovery is one of the most challenging research fields that contributes to the birth of novel drugs for therapeutic use. Due to the complexity and intricate nature of the research, lengthy processes are involved in identifying potential hit molecules for a therapeutic target. To shorten the time required to reach the hit-to-lead stage, computer-aided drug design (CADD) has been used to expedite the process and reduce laboratory expenses. Common strategies used within CADD involve structure-based drug design (SBDD) and ligand-based drug design (LBDD). Both strategies were used extensively in two projects showing the complementarity of each strategy throughout the process. In this work, two separate drug discovery projects are detailed: Design, synthesis and molecular docking study of novel tetrahydrocurcumin analogues as potential sarcoplasmic-endoplasmic reticulum calcium ATPases (SERCA) inhibitors – details the identification, synthesis and testing of potential hit candidate(s) targeting SERCA by using SBDD Filamenting temperature-sensitive mutant Z (FtsZ) as therapeutic target in ligand-based drug design – details the identification, synthesis and testing of potential hit molecule(s) targeting FtsZ In the first project, homology modelling and virtual compound library screening were utilised as the SBDD methods to identify potential hit molecules for testing in P-type calcium ATPases such as SERCA. Preliminary results have found compound 20, an analogue of tetrahydrocurcumin, to show some SERCA inhibitory effect at 300µM based on a SERCA-specific calcium signalling assay performed via fluorometric imaging plate reader. Molecular docking study has also reflected this outcome with desirable ligand-protein binding energies found for 20 when compared with other tested ligands. Pharmacophore screening was used as the main LBDD method in the second project to identify probable hit candidates targeting FtsZ. Potential ligands were synthesised, and tested for antibacterial effect in Bacillus Subtilis strain 168 (Bs168) and Streptococcus pneumoniae strain R6 (SpnR6) cells. One of the tetrahydrocurcumin analogues, compound 4, was found to have minimum inhibitory concentration (MIC) ≤ 10 µM in Bs168 cells and ≤ 2 µM in spnR6 cells. The IC50 values for 4 were 9.1 ± 0.01 µM and 1 ± 0.01 µM in Bs168 and SpnR6 cells respectively. The MIC of 4 was found to be very similar to the MIC of compound 1, a known hit compound targeting against Bs168 cells. On the other hand, the MIC of 4 was lower than the MIC (> 64 µg/mL) of a well-known FtsZ inhibitor, PC190723, against S. pneumoniae. Subsequent molecular docking analyses were completed to evaluate the ligand-protein binding energies to correlate against the testing results. Both compounds 20 and 4 possess some structural similarities and differences that may confer their different effects in these protein targets, which render both with potentials to become the next lead molecules for future development.