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Rheumatoid arthritis (RA) is a chronic immune-related condition, primarily of joints, and is highly disabling and painful. The inhibition of Janus kinase (JAK)-related cytokine signaling pathways using small molecules is prevalent nowadays. The JAK family belongs to nonreceptor cytoplasmic protein tyrosine kinases (PTKs), including JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). JAK1 has received significant attention after being identified as a promising target for developing anti-RA therapeutics. Currently, no crystal structure is available for JAK1 in complex with the next-generation anti-RA drugs. In the current study, we investigated the mechanism of binding of baricitinib, filgotinib, itacitinib, and upadacitinib to JAK1 using a combined method of molecular docking, molecular dynamics simulation, and binding free energy calculation via the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) scheme. We found that the calculated binding affinity decreases in the order upadacitinib > itacitinib > filgotinib > baricitinib. Due to the increased favorable intermolecular electrostatic contribution, upadacitinib is more selective to JAK1 compared to the other three inhibitors. The cross-correlation and principal component analyses showed that different inhibitor bindings significantly affect the binding site dynamics of JAK1. Furthermore, our studies indicated that the hydrophobic residues and hydrogen bonds from the hinge region (Glu957 and Leu959) of JAK1 played an essential role in stabilizing the inhibitors. Protein structural network analysis reveals that the total number of links and hubs in JAK1/baricitinib (354, 48) is more significant than those in apo (328, 40) and the other three complexes. The JAK1/baricitinib complex shows the highest probability of the highest-ranked community, indicating a compact network of the JAK1/baricitinib complex, consistent with its higher stability than the rest of the four systems. Overall, our study may be crucial for the rational design of JAK1-selective inhibitors with better affinity.

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Malaria causes millions of deaths every year. The malaria parasite spends a substantial part of its life cycle inside human erythrocytes. Inside erythrocytes, it synthesizes and displays various proteins onto the erythrocyte surface, such as Plasmodium falciparum erythrocytic membrane protein-1 (PfEMP1). This protein contains cysteine-rich interdomain region (CIDR) domains which have many subtypes based on sequence diversity and can cross-talk with host molecules. The CIDRα1.4 subtype can attach host endothelial protein C receptor (EPCR). This interaction facilitates infected erythrocyte adherence to brain endothelium and subsequent development of cerebral malaria. Through molecular dynamics simulations in conjunction with the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) method, we explored the mechanism of interaction in the CIDRα1–EPCR complex. We examined the structural behavior of two CIDRα1 molecules (encoded by HB3-isolate var03-gene and IT4-isolate var07-gene) with EPCR unbound and bound (complex) forms. HB3var03CIDRα1 in apo and complexed with EPCR was comparatively more stable than IT4var07CIDRα1. Both of the complexes adopted two distinct conformational energy states. The hydrophobic residues played a crucial role in the binding of both complexes. For HB3var03CIDRα1–EPCR, the dominant energetic components were total polar interactions, while in IT4var07CIDRα1–EPCR, the primary interaction was van der Waals and nonpolar solvation energy. The study also revealed details such as correlated conformational motions and secondary structure evolution. Further, it elucidated various hotspot residues involved in protein–protein recognition. Overall, our study provides additional information on the structural behavior of CIDR molecules in unbound and receptor-bound states, which will help to design potent inhibitors.