Pratap SinghRaman Anirudh, Kumar Durgesh, Kumari Kamlesh, Jain Pallavi, Bahadur Indra, Abedigamba Oyirwoth P, Preetam Amreeta, Singh Prashant
Department of Chemistry, Atma Ram Sanatan Dharma College, University of Delhi, Delhi, India.
Department of Chemistry, Maitreyi College, University of Delhi, New Delhi, India.
Chem Biodivers. 2024 Dec;21(12):e202401241. doi: 10.1002/cbdv.202401241. Epub 2024 Oct 18.
The non-structural protein (nsP2 & nsP3) of the Chikungunya virus (CHIKV) is responsible for the transmission of viral infection. The main role of non-structural proteins are involved in the transcription process at an early stage of the infection. In this work, authors have studied the impact of nsP2 and nsP3 of CHIKV on hormones present in the human body using a computational approach. The ten hormones of chemical properties such as 4-Androsterone-2,17-dione, aldosterone, androsterone, corticosterone, cortisol, cortisone, estradiol, estrone, progesterone and testosterone were taken as a potency. From the molecular docking, the binding energy of the complexes is estimated, and cortisone was found to be the highest negative binding energy (-6.57 kcal/mol) with the nsP2 and corticosterone with the nsP3 (-6.47 kcal/mol). This is based on the interactions between hormones and nsP2/nsP3, which are types of noncovalent intermolecular interactions categorized into three types: electrostatic interactions, van der Waals (vdW) interactions, and hydrogen-bonding (H-bonding) interactions. To validate the docking results, additional molecular dynamics simulations and MM-GBSA methods were performed. The change in enthalpy, entropy, and free energy were calculated using MM-GBSA methods. The nsP2 and nsP3 of CHIKV interact strongly with the cortisone and corticosterone with free energy changes of -20.55 & -36.08 kcal/mol, respectively. Methods: The crystal structures of 3TKR and 3GPO proteins of nsP2 and nsP3 were extracted from the RCSB Protein Data Bank. Initially, unnecessary atoms like extra cations or anions and missing explicit hydrogen atoms were removed and added from the native domain of nsP2 and nsP3. The alignment of coordinated in the native domain was performed using Chimera and Notepad tools. The molecular docking of protein and ligand was performed usingAutoDock tool; it is essential for the prediction of the orientation of the ligand into the cavity of the target protein based on binding affinity. Based on thermodynamic parameters, MD Simulations were employed to calculate the change in binding free energies of various complexes followed by a change in enthalpy and entropy with time. According to MD production, the CPPTAJ and PTRAJ programs were used to analyse the trajectories, such as dynamic stability (RMSD), residual fluctuation (RMSF), compatibility, and hydrogen bonds of the newly formed complexes. After that, the Density Functional Theory (DFT) were used to calculate the electronic properties of selected molecules by Gaussian 16 on applying the B3LYP method with the 6-311G (d, p) basis set.
基孔肯雅病毒（CHIKV）的非结构蛋白（nsP2和nsP3）负责病毒感染的传播。非结构蛋白的主要作用涉及感染早期的转录过程。在这项工作中，作者使用计算方法研究了CHIKV的nsP2和nsP3对人体中存在的激素的影响。选取了具有化学性质的十种激素，如4-雄甾酮-2,17-二酮、醛固酮、雄甾酮、皮质酮、皮质醇、可的松、雌二醇、雌酮、孕酮和睾酮作为研究对象。通过分子对接，估计了复合物的结合能，发现可的松与nsP2的结合能最高为负（-6.57 kcal/mol），皮质酮与nsP3的结合能为负（-6.47 kcal/mol）。这是基于激素与nsP2/nsP3之间的相互作用，这些相互作用属于非共价分子间相互作用，分为三种类型：静电相互作用、范德华（vdW）相互作用和氢键（H键）相互作用。为了验证对接结果，还进行了额外的分子动力学模拟和MM-GBSA方法。使用MM-GBSA方法计算了焓、熵和自由能的变化。CHIKV的nsP2和nsP3分别与可的松和皮质酮强烈相互作用，自由能变化分别为-20.55和-36.08 kcal/mol。方法：从RCSB蛋白质数据库中提取nsP2和nsP3的3TKR和3GPO蛋白的晶体结构。最初，从nsP2和nsP3的天然结构域中去除不必要的原子，如额外的阳离子或阴离子，并添加缺失的显式氢原子。使用Chimera和Notepad工具对天然结构域中的坐标进行比对。使用AutoDock工具进行蛋白质和配体的分子对接；这对于基于结合亲和力预测配体在靶蛋白腔中的取向至关重要。基于热力学参数，采用分子动力学模拟计算各种复合物结合自由能的变化，以及焓和熵随时间的变化。根据分子动力学模拟结果，使用CPPTAJ和PTRAJ程序分析轨迹，如新形成复合物的动态稳定性（RMSD）、残余波动（RMSF）、兼容性和氢键。之后，使用密度泛函理论（DFT）通过高斯16在应用B3LYP方法和6-311G（d，p）基组的情况下计算所选分子的电子性质。
