Biochemistry, mechanistic intricacies, and therapeutic potential of Antimicrobial Peptides: an alternative to traditional Antibiotics.

The emergence of drug-resistant strains of pathogens becomes a major obstacle to treating human diseases. Antibiotics and antivirals are in the application for a long time but now these drugs are not much effective anymore against disease-causing drug-resistant microbes and gradually it is becoming a serious complication worldwide. The development of new antibiotics cannot be a stable solution to treat drug-resistant strains due to their evolving nature and escaping antibiotics. At this stage, antimicrobial peptides (AMPs) may provide us with novel therapeutic leads against drug-resistant pathogens. Structurally, antimicrobial peptides are mostly α-helical peptide molecules with amphiphilic properties that carry the positive charge (cationic) and it belong to host defence peptides. These positively charged AMPs can interact with negatively charged bacterial cell membranes and may cause the alteration in electrochemical potential on bacterial cell membranes and consequently lead to the death of microbial cells. In the present study, we will elaborate on the implication of AMPs in the treatment of various diseases along with their specific structural and functional properties. This review will provide information which assists in the development of new synthetic peptide analogues to natural AMPs. These analogues will eliminate the limitations of natural AMPs like toxicity and severe hemolytic activities.

Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach.

Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αE'-ßf' loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme.

Structural differences in 3C-like protease (Mpro) from SARS-CoV and SARS-CoV-2: molecular insights revealed by Molecular Dynamics Simulations.

Novel coronavirus SARS-CoV-2 has infected millions of people with thousands of mortalities globally. The main protease (Mpro) is vital in processing replicase polyproteins. Both the CoV's Mpro shares 97% identity, with 12 mutations, but none are present in the active site. Although many therapeutics and vaccines are available to combat SARS-CoV-2, these treatments may not be practical due to their high mutational rate. On the other hand, Mpro has a high degree of conservation throughout variants, making Mpro a stout drug target. Here, we report a detailed comparison of both the monomeric Mpro and the biologically active dimeric Mpro using MD simulation to understand the impact of the 12 divergent residues (T35V, A46S, S65N, L86V, R88K, S94A, H134F, K180N, L202V, A267S, T285A and I286L) on the molecular microenvironment and the interaction between crucial residues. The present study concluded that the change in the microenvironment of residues at the entrance (T25, T26, M49 and Q189), near the catalytic site (F140, H163, H164, M165 and H172) and in the substrate-binding site (V35, N65, K88 and N180) is due to 12 mutations in the SARS-CoV-2 Mpro. Furthermore, the involvement of F140, E166 and H172 residues in dimerization stabilizes the Mpro dimer, which should be considered. We anticipate that networks and microenvironment changes identified here might guide repurposing attempts and optimization of new Mpro inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02089-6.

Designing multi-epitope based peptide vaccine targeting spike protein SARS-CoV-2 B1.1.529 (Omicron) variant using computational approaches.

Millions of lives have been infected since the SARS-CoV-2 outbreak in 2019. The high human-to-human transmission rate has warranted a need for a vaccine to protect people. Although some vaccines are in use, due to the high mutation rate in the SARS-CoV-2 multiple variants, the current vaccines may not be sufficient to immunize people against new variant threats. One of the emerging concern variants is B1.1.529 (Omicron), which carries ~ 30 mutations in the Spike protein (S) of SARS-CoV-2 and is predicted to evade antibody recognition even from vaccinated people. We used a structure-based approach and an epitope prediction server to develop a Multi-Epitope based Subunit Vaccine (MESV) involving SARS-CoV-2 B1.1.529 variant spike glycoprotein. The predicted epitope with better antigenicity and non-toxicity was used for designing and predicting vaccine construct features and structure models. In addition, the MESV construct In silico cloning in the pET28a expression vector predicted the construct to be highly translational. The proposed MESV vaccine construct was also subjected to immune simulation prediction and was found to be highly antigenic and elicit a cell-mediated immune response. Therefore, the proposed MESV in the present study has the potential to be evaluated further for vaccine production against the newly identified B1.1.529 (Omicron) variant of concern. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02027-6.