Quantum Biochemical Investigation of Lys49-PLA2 from Bothrops moojeni.

Envenomation via snakebites occurs largely in areas where it is harder to access the hospital. Its mortality rate and sequelae acquired by the survivors symbolize a big challenge for antivenom therapy. In particular, the homologous phospholipase A2 (Lys49-PLA2) proteins can induce myonecrosis and are not effectively neutralized by current treatments. Thus, by taking advantage of crystallographic structures of Bothrops moojeni Lys49-PLA2 complexed with VRD (varespladib) and AIN (aspirin), a quantum biochemistry study based on the molecular fractionation with conjugate cap scheme within the density functional theory formalism is performed to unveil these complexes' detailed interaction energies. The calculations revealed that important interactions between ligands and the Lys49-PLA2 pocket could occur up to a pocket radius of r = 6.5 (5.0 Å) for VRD (AIN), with the total interaction energy of the VRD ligand being higher than that of the AIN ligand, which is well-correlated with the experimental binding affinity. Furthermore, we have identified the role played by the amino acids LYS0069, LYS0049, LEU0005, ILE0009, CYS0029, GLY0030, HIS0048, PRO0018, ALA0019, CYS0045, TYR0052, TYR0022, PRO0125*, and PHE0126* (LYS0069, LYS0049, GLY0032, LEU0002, and LEU0005) in the VRD↔Lys49-PLA2 (AIN↔Lys49-PLA2) complex. Our simulations are a valuable tool to support the big challenge for neutralizing the damages in victims of snakebites.

New ethionamide boosters and EthR2: structural and energetic analysis.

Ethionamide (ETH) is a high-profile drug for the treatment of patients with multidrug-resistant Mycobacterium tuberculosis and, in order to produce its inhibitory effects, it needs to be bioactivated by monooxygenase EthA. This process is under the control of the transcriptional repressors EthR and EthR2, so that their inhibition results in the boosting of ethionamide activation. Herein, through crystallographic data and computer simulations, we calculated the interaction binding energies of four inhibitors with improved in vitro potency, namely BDM76060 (PDB ID: 6HS1), BDM72201 (PDB ID: 6HRX), BDM76150 (PDB ID: 6HS2) and BDM72719 (PDB ID: 6HRY), in complexes with the transcriptional repressor EthR2, using density functional theory (DFT) within the molecular fractionation with conjugated caps (MFCC) approach. It was observed that these ligands share the same binding site within a 10.0 Å radius of the EthR2 protein; however, their structural particularities have a significant impact on the global energies of systems. The BDM72201 and BDM72719 components are weakly attached to the binding site, while BDM76060 and BDM76150 components produce stronger bonds, corroborating with experimental studies demonstrating that BDM76060 and BDM76150 are more successful in producing inhibitory effects. BDM76060 and BDM76150 have many functional groups that increase the contact surface with the protein and attract a more significant number of amino acid residues, being able to produce polarities that generate stronger interactions. In the current scenario of a growing number of cases of bacterial resistance, the obtained data can be used to guide clinical trials of these inhibitors and other inhibitors that act on the alternative EthR2 pathway, focusing on improving the activity of ethionamide, its effectiveness, a reduction in the treatment time and exposure to cytotoxic effects.

Blockade of the checkpoint PD-1 by its ligand PD-L1 and the immuno-oncological drugs pembrolizumab and nivolumab.

We investigate the interaction between the programmed cell death protein 1 (PD-1) and the programmed cell death ligand 1 (PD-L1), as well as the immuno-oncological drugs pembrolizumab (PEM), and nivolumab (NIV), through quantum chemistry methods based on the Density Functional Theory (DFT) and the molecular fractionation with conjugate caps (MFCC) scheme, in order to map their hot-spot regions. Our results showed that the total interaction energy order of the three complexes is in good agreement with the experimental binding affinity order: PD-1/PEM > PD-1/NIV > PD-1/PD-L1. Besides, a detailed investigation revealed the energetically most relevant residue-residue pairs-interaction for each complex. Our computational results give a better understanding of the interaction mechanism between the protein PD-1 and its ligands (natural and inhibitors), unleashing the immune surveillance to destroy the cancer cells by decreasing their immune evasion. They are also an efficient alternative towards the development of new small-molecules and antibody-based drugs, pointing out to new treatments for cancer therapy.