Computer-aided rational design and synthesis of new potential antihypertensive agents among 1,2,3-triazole-containing nifedipine analogs

Abstract

1,2,3-Triazole-containing Nifedipine analogues offer the opportunity to increase biostability, bioavailability, efficacy and binding selectivity to target receptors. Here, we applied a computer-aided rational design for identifying new Nifedipine analogues containing a 1,2,3-triazole moiety. First, a new chemical library of 796 derivatives combining the DHP fragment and 1,2,3-triazole moiety was generated. Second, to reduce the library size, the library was pre-filtered using two 3D-pharmacophore models with different complexity, which allowed us to gradually reduce the chemical space, ending up with 26 hit candidates. Molecular docking calculations against the rCav1.1 receptor allowed the identification of eight derivatives 5a-h, characterized by the binding affinity towards the rCav1.1 receptor of the same level as approved Nifedipine-like drugs. Next, our molecular docking results were used to guide and optimize the retrosynthetic approaches for new analogues of Nifedipine as promising antihypertensive agents. So, a retrosynthetic approach for Nifedipine analogues with a 1,2,3-triazole ring in position 4 was proposed. Finally, eight analogues 5a-h determined by molecular docking calculations were synthesized using the suggested retrosynthetic approach. The aim of this study is to identify new Nifedipine analogues using a computer-aided drug design and a retrosynthetic approach. Materials and Methods. The organic synthesis of new Nifedipine analogues containing a 1,2,3-triazole moiety. Computer-aided drug design of new DHP derivatives using pharmacophore screening and molecular docking calculations. Results. Molecular docking of new Nifedipine analogues made it possible to estimate the binding affinity of new Nifedipine derivatives to the rCav1.1 receptor. Pharmacophore screening of a chemical library of analogues, consisting of 796 derivatives, allowed gradually reducing the chemical space and obtaining 26 candidates with high affinity to the rCav1.1 receptor. Using the method of molecular docking, eight hits 5a-h were identified, and the synthesis of the recommended compounds was proposed and performed. Conclusions. The results of molecular docking showed that Nifedipine analogues are characterized by binding affinity to the rCav1.1 receptor at the same level as approved Nifedipine-like drugs. Pharmacophore screening and molecular docking calculations indicate key features of the ligand-receptor interaction that can guide and optimize the synthesis of new Nifedipine analogues as promising new antihypertensive agents. A retrosynthetic approach was proposed, and the recommended compounds were synthesized