Volume-1

First published on the web on Dec 29, 2025

About Cover Image: TRIM71 with a novel small molecule inhibitor with improved PK/PD properties

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Structure-Based Drug Design to Discover Potential Hit Molecules for the Trim71 protein to prevent Congenital Hydrocephalus

Congenital Hydrocephalus (CH) is a condition characterized by excessive accumulation of cerebrospinal fluid (CSF) in the brain's ventricles, often linked to mutations in the Trim71 gene. These mutations frequently result in a gain-of-function in the encoded LIN-41 protein, disrupting stem cell differentiation and neural development. Currently, no specific small-molecule inhibitors exist for TRIM71. This study utilizes structure-based drug design to identify potential hit molecules targeting the NHL domain of the TRIM71 protein. Using the Accelera PlayMolecule platform and molecular docking simulations, we screened libraries for compounds with favorable binding energies and drug-likeness. We identified Compound E as a promising candidate, exhibiting strong binding interactions (IC50 potential) and favorable blood-brain barrier permeability. These findings offer a potential therapeutic pathway for preventing the progression of CH.

Veer Bhatia and Divya Ramamoorthy

E3 Ubiquitin Ligases – Structure, Function, Disease Implications, and Therapeutic Options

Hrishikesh Satish and Divya Ramamoorthy

Affecting hundreds of thousands of people around the world, Huntington’s Disease is a neurodegenerative disorder causing involuntary movements, poor-decision making, nervous system shutdown, and ultimately death. The aim of this project was to identify molecules as inhibitors to limit the disease-causing mutation, known as mHTT. We used the PDB 4FEB in this study. Three groups of compounds, CNS compounds, mHTT inhibitors, and peptidomimetics that we screened in the study. In addition, we analyzed the binding site and created a docking grid to prepare the mHTT protein for SP and XP docking. We also performed Wikprop analysis, which gave us the log BB, molMW, and PercentHumanOralAbsorption of the ligand. Finally, we created ligand interaction diagrams between the top-performing ligands and the 4FEB chain to demonstrate the key interactions. While the top-scoring ligands are likely not directly suitable for clinical use in treating or preventing Huntington’s Disease, our goal is to continue researching ligands that can drive the design of new compounds for effectively targeting and defeating Huntington’s Disease.

Structure-Based Drug Discovery of New Compounds Targeting Exon 1 N-terminus Region of Mutant Huntingtin

Yash Jaju and Divya Ramamoorthy

E3 ubiquitin ligases are essential mediators in the ubiquitination cascade, governing protein degradation, DNA repair, and immune responses. This review examines the three primary classes of E3 ligases—HECT, RING, and RBR—detailing their unique structural architectures and catalytic mechanisms. We explore how structural motifs, such as the RING finger and the HECT domain, facilitate the transfer of ubiquitin to substrates. Furthermore, we discuss the clinical implications of E3 ligase dysregulation in cancer and neurodegenerative disorders, alongside emerging therapeutic strategies like PROTACs. By analyzing specific ligases such as WWP2, TRIM31, and TRIM71, this paper highlights the potential of targeting these enzymes to address complex human diseases.

Targeting Rank1 protein towards the cure of Osteomyelitis using small molecule inhibitors

Anushka Ivatury and Divya Ramamoorthy

The study targets RANKL using small molecule inhibitors in order to mitigate bone resorptions and protect immune health. Through protein preparation, ligand optimization, and molecular docking, we were able to analyze different small molecular inhibitors as well as antiviral compounds. Looking for molecular inhibitors and antiviral compounds with topmost docking scores, our results indicated S1774 to be a potential inhibitor with a docking score of -5.035 kcal/mol. In the end, we identified possible inhibitors to mitigate a bone disease like osteomyelitis.

Frontotemporal Dementia: Discovery of Novel TTK Kinase Inhibitors

Hasini Gajendran and Divya Ramamoorthy

Frontotemporal dementia (FTD) is a devastating neurodegenerative disorder for which there are currently no disease‑modifying treatments. In this project, we explored threonine tyrosine kinase (TTK) as a potential therapeutic target because of its role in phosphorylating Tau, a key protein implicated in FTD. Using the Schrödinger Suite 2024‑3, we performed detailed docking studies, cross‑structure comparisons, and substructure‑based ligand design. Several candidate compounds demonstrated stronger predicted binding (docking scores down to –15 kcal/mol) than previously known inhibitors and also showed favorable absorption and blood–brain permeability profiles when assessed with QikProp. These findings provide a computational foundation for future experimental validation and point toward new avenues for the treatment of FTD.

Analyzing AKT1 Mutants Towards the Progression of Meningioma

Elroy Pulickathadam and Divya Ramamoorthy

Meningioma, a common primary brain tumor, is frequently driven by recurrent somatic mutations in the AKT1 gene, particularly the E17K mutation, which leads to constitutive kinase activation and unchecked cell proliferation. This study investigates the structural basis of AKT1 activation and the potential for targeted therapeutic intervention using high-resolution crystal structures (PDB: 8UW7 and 8UW9). Notably, the E17K mutation enables a unique neo-zinc chelation mechanism that allows for mutation-specific inhibitor selectivity. Residue scanning analysis identified ASP 274 as a critical residue for protein stability, where specific substitutions (e.g., to MET, GLN, or GLU) significantly increased stability compared to other mutations. These findings elucidate the interaction landscape of AKT1 inhibitors and provide a foundation for the rational design of more precise, mutation-specific treatments to improve therapeutic outcomes for meningioma patients.