Umar Abdullahi B, Uzairu Adamu
Department of Chemistry, Faculty of Physical Sciences, Ahmad Bello University, Zaria, Kaduna State, Nigeria.
J Taibah Univ Med Sci. 2023 Mar 2;18(5):1000-1010. doi: 10.1016/j.jtumed.2023.02.010. eCollection 2023 Oct.
The V600E-BRAF protein kinase is an attractive and essential therapeutic target in melanoma and other tumors. However, because of its resistance to the known inhibitors and side effects of some identified inhibitors, new potent inhibitors need to be identified.
In the present work, in silico strategies such as the molecular docking simulation, DFT (Density-Functional-Theory) computations, and pharmacokinetic evaluation were used to determine potential V600E-BRAF inhibitors from a set of 31 synthesized novel flavone-based arylamides.
The docking result demonstrated that four compounds (10, 11, 28, and 31) had acceptable docking scores (MolDock score of -167.523 kcal mol, -158.168 kcal mol, -160.581 kcal mol,-162.302 kcal mol, and a Rerank score of -124.365, -129.365, -135.878 and -117.081, respectively) appeared as most active and potent V600E-BRAF inhibitors that topped vemurafenib (-158.139 and -118.607 kcal mol). The appearance of H-bonds and hydrophobic interactions with essential residues for V600E-BRAF proved the high stability of these complexes. The energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters was computed using DFT. The frontier molecular-orbital surfaces and electrostatic potentials (EPs) were investigated to demonstrate the charge-density distributions that might be linked to anticancer activity. Similarly, the chosen compounds revealed superior pharmacological properties according to the drug-likeness rules (bioavailability) and pharmacokinetic properties.
The chosen compounds were recognized as potent V600E-BRAF inhibitors with superior pharmacokinetic properties and could be promising cancer drug candidates.
V600E-BRAF蛋白激酶是黑色素瘤和其他肿瘤中一个具有吸引力且至关重要的治疗靶点。然而，由于其对已知抑制剂具有抗性以及某些已鉴定抑制剂存在副作用，需要鉴定新的强效抑制剂。
在本研究中，采用了诸如分子对接模拟、密度泛函理论（DFT）计算和药代动力学评估等计算机辅助策略，从一组31种合成的新型黄酮基芳基酰胺中确定潜在的V600E-BRAF抑制剂。
对接结果表明，四种化合物（10、11、28和31）具有可接受的对接分数（MolDock分数分别为-167.523 kcal mol、-158.168 kcal mol、-160.581 kcal mol、-162.302 kcal mol，重排分数分别为-124.365、-129.365、-135.878和-117.081），表现为最具活性和强效的V600E-BRAF抑制剂，超过了维莫非尼（-158.139和-118.607 kcal mol）。与V600E-BRAF的关键残基形成氢键和疏水相互作用，证明了这些复合物的高稳定性。使用DFT计算了前线分子轨道的能量，如最高占据分子轨道（HOMO）、最低未占据分子轨道（LUMO）、能隙和其他反应性参数。研究了前线分子轨道表面和静电势（EPs），以证明可能与抗癌活性相关的电荷密度分布。同样，根据类药规则（生物利用度）和药代动力学性质，所选化合物显示出优异的药理特性。
所选化合物被认为是具有优异药代动力学性质的强效V600E-BRAF抑制剂，有望成为癌症候选药物。
