In silico biochemical de novo drug design of valproic acid derivatives to suppress cancerous dna: comprehensive molecular docking, molecular dynamics, 1 h nmr, adme

Objective: This comprehensive in silico computational and theoretical biochemistry/organic chemistry research study covers the inhibition methodologies of 1-BNA, which is an essential template for cancer- suppressing research. By disrupting the minor groove domain binding site of the DNA template 1-BNA dodecamer, three de novo drug candidate molecules via derivatization of anti-epileptic valproic acid (VPA) drug were designed. Methods: Calf thymus DNA (ct-DNA) sequence d(CGCGAATTCGCG)2 dodecamer (PDB ID: 1BNA) was obtained from the Protein Data Bank to study. Molecular docking simulations, the most updated docking programs of AutoDock Vina and PyRx were utilized. Molecular dynamics (MD) simulations and Absorption, distribution, metabolism and excretion (ADME) analyses were employed by Schrödinger’s Desmond software. Results: Thorough in silico results of three new derivatized analogues of VPA showed that chloro-derivatized analogue with its -9.6 kcal/mol docking score and 297.2 µM inhibition constant (IC) has a much better indication in the suppression where isopropyl and fluoro derivatized analogues possess -9.1 kcal/mol docking score with 483.8 µM IC and - 8.3 kcal/mol docking score with 896.2 µM IC respectively compared to the results of pristine VPA’s -8.2 kcal/mol docking score with 863.6 µM IC. Along with the detailed ADME results, isopropyl and chloro- derivatized ligands prove their worth of being a new drug candidate. Conclusion: All results proved that the de novo derivatives of VPA illustrate better docking scores (better suppression) along with better ICs and oral absorption percentage values, meaning that the analogues possess better indications compared to pristine VPA toward the suppression of cancerous cell template DNA.