Gyebi Gideon A, Ogunyemi Oludare M, Adefolalu Adedotun A, Rodríguez-Martínez Alejandro, López-Pastor Juan F, Banegas-Luna Antonio J, Pérez-Sánchez Horacio, Adegunloye Adegbenro P, Ogunro Olalekan B, Afolabi Saheed O
Department of Biochemistry, Bingham University, Karu, Nigeria.
Human Nutraceuticals and Bioinformatics Research Unit, Department of Biochemistry, Salem University, Lokoja, Nigeria.
J Mol Struct. 2022 Aug 15;1262:133019. doi: 10.1016/j.molstruc.2022.133019. Epub 2022 Apr 12.
Despite the ongoing vaccination against the life-threatening COVID-19, there is need for viable therapeutic interventions. The S-adenosyl-l-Methionine (SAM) dependent 2-O'-ribose methyltransferase (2'-O-MTase) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a therapeutic target against COVID-19 infection. In a bid to profile bioactive principles from natural sources, a custom-made library of 226 phytochemicals from African medicinal plants with especially anti-malarial activity was screened for direct interactions with SARS-CoV-2 2'-O-MTase (S2RMT) using molecular docking and molecular dynamics (MD) simulations as well as binding free energies methods. Based on minimal binding energy lower than sinefungin (a reference methyl-transferase inhibitor) and binding mode analysis at the catalytic site of S2RMT, a list of 26 hit phytocompounds was defined. The interaction of these phytocompounds was compared with the 2'-O-MTase of SARS-CoV and MERS-CoV. Among these compounds, the lead phytocompounds (LPs) viz: mulberrofuran F, 24-methylene cycloartenol, ferulate, 3-benzoylhosloppone and 10-hydroxyusambarensine interacted strongly with the conserved KDKE tetrad within the substrate binding pocket of the 2'-O-MTase of the coronavirus strains which is critical for substrate binding. The thermodynamic parameters analyzed from the MD simulation trajectories of the LPs-S2RMT complexes presented an eminent structural stability and compactness. These LPs demonstrated favorable druggability and ADMET properties over a diverse array of molecular computing descriptors. The LPs show promising prospects in the disruption of S2RMT capping machinery . However, these LPs should be validated via and experimental models.
尽管正在进行针对危及生命的新冠病毒病（COVID-19）的疫苗接种，但仍需要可行的治疗干预措施。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的S-腺苷-L-甲硫氨酸（SAM）依赖性2'-O-核糖甲基转移酶（2'-O-MTase）是对抗COVID-19感染的一个治疗靶点。为了剖析天然来源的生物活性成分，使用分子对接、分子动力学（MD）模拟以及结合自由能方法，对一个由226种具有抗疟活性的非洲药用植物的植物化学物质定制库进行筛选以寻找与SARS-CoV-2 2'-O-MTase（S2RMT）的直接相互作用。基于低于辛弗林（一种参考甲基转移酶抑制剂）的最小结合能以及在S2RMT催化位点的结合模式分析，确定了26种有活性的植物化合物清单。将这些植物化合物的相互作用与SARS-CoV和MERS-CoV的2'-O-MTase进行了比较。在这些化合物中，先导植物化合物（LPs）即：桑呋喃F、24-亚甲基环阿尔廷醇、阿魏酸、3-苯甲酰霍斯洛波酮和10-羟基乌桑巴任碱与冠状病毒株2'-O-MTase底物结合口袋内保守的KDKE四联体强烈相互作用，该四联体对于底物结合至关重要。从LPs-S2RMT复合物的MD模拟轨迹分析的热力学参数显示出显著的结构稳定性和紧凑性。与一系列不同的分子计算描述符相比，这些LPs表现出良好的成药可能性和ADMET性质。这些LPs在破坏S2RMT封端机制方面显示出有前景的前景。然而，这些LPs应通过实验模型进行验证。
