Design and Computational Docking Exploration of Innovative Thiadiazole Analogues Targeting Cancer Activity

Melanoma, arising from uncontrolled melanocyte proliferation, is treatable in its early stages
but poses significant challenges in advanced cases. This study aimed to design and evaluate
novel thiadiazole derivatives as potential anti-cancer agents targeting the BRAF protein using
3D-QSAR modeling and molecular docking. A dataset of 51 reported BRAF inhibitors was
analyzed using the Schrödinger suite, and the Gaussian-based QSAR model showed strong
predictive reliability (r² = 0.93, r²cv = 0.47, SE = 0.2, F ratio = 80.3), with field contributions
of steric (0.29), hydrophobic (0.24), hydrogen bond donor (0.18), electrostatic (0.188), and
hydrogen bond acceptor (0.08). Guided by these findings, 25 novel thiadiazole derivatives were
designed and subjected to docking studies in PyRx. Among them, compound IA25
demonstrated the best binding affinity (−9.7 kcal/mol), comparable to the standard Dabrafenib,
forming two hydrogen bonds with Asn221 and Phe209 residues. Other derivatives showed
scores ranging from −8.0 to −9.6 kcal/mol, with 10 shortlisted for further study. These results
highlight the critical role of hydrogen bond donor and acceptor substituents on the thiadiazole
ring in BRAF inhibition and suggest IA25 as a promising anti-cancer lead.