Structural Biology

NON-COMMUNICABLE DISEASES / Cancer

Research Interests

We aim to develop structure-based therapeutics for ASCVD and cancer, reducing mortality rates and enhancing the quality of life through targeted therapies. Our work involves CADD to identify and optimize drug candidates validated through in vitro and in vivo models. We actively seek collaborations with industry partners to advance lead candidates towards IND-enabling studies and clinical trials.

Description of Research

Tackling Atherosclerosis with the Cutting-Edge Approaches Targeting LOX-1 Receptor

  • Clinical Significance: Cardiovascular diseases (CVD), including heart attacks and strokes, are the leading cause of death globally, accounting for approximately 32% of all deaths in 2019. A significant underlying cause of CVD is atherosclerosis, which is characterized by the accumulation of plaques in the arteries. The rising incidence of early onset of myocardial infarction (MI) in individuals under 45 underscores the urgent need for new therapeutic strategies. 
    • Hypothesis: Recent research, including those from our group, have demonstrated that the binding and uptake of oxidized low-density lipoprotein (oxLDL) through the lectin-like oxLDL receptor, LOX-1, plays a crucial role in atherosclerosis progression, making LOX-1 a promising therapeutic target. 
    • Approach: We focus on a structure-based drug discovery approach to target the LOX-1 receptor. Our group has determined high-resolution crystal structures of the LOX-1 bound to various inhibitor molecules. The deeper insights gained from these structures have enabled us to identify small molecule inhibitors that effectively block the interaction between oxLDL and LOX-1, potentially halting the early stages of plaque formation.
    • Current Findings: Our group has performed preclinical studies using the apolipoprotein E (ApoE-/-) mouse, a well-established in vivo model of atherosclerosis, and demonstrated significant anti-atherogenic activity for the selected compounds. These results have helped us identify lead molecules that are currently undergoing further optimization to enhance their potency, selectivity, and pharmacokinetic properties. 
    • Research Goals: We are currently conducting preclinical testing in a more advanced ApoE-/- Fbn1C1041G+/-mouse model, a valuable tool for investigating the mechanisms underlying plaque instability and identifying potential therapeutics for preventing plaque rupture and subsequent cardiovascular events such as heart attack and stroke. We seek to protect our discoveries through intellectual property rights (IPR) and initiate IND-enabling studies in collaboration with industry partners, laying the groundwork for future clinical trials in humans. 
    • Potential Impact: The successful development of LOX-1 inhibitors has the potential to transform the current therapeutic landscape for cardiovascular disease. By targeting a key driver of atherosclerosis, these novel therapeutics could not only slow down disease progression but also reduce the risk of heart attacks and strokes, significantly improving patient outcomes and quality of life.

Targeting Vitamin C Recycling: A Novel Approach to Cancer Therapy

  • Clinical Significance: Cancer ranks as the second leading cause of death worldwide, responsible for approximately 9.6 million deaths in 2018, equating to 1 in 6 deaths (WHO). There is a pressing need for novel targeted therapies in cancer treatment with improved precision, reduced side effects, and potential to overcome resistance. Innovative therapies are essential for improved patient outcomes, extending survival, and enhancing the quality of life for cancer patients.
    • Hypothesis: Humans cannot synthesize vitamin C, a key co-factor and a major antioxidant. Cancer cells exhibit an increased demand for vitamin C due to their rapid growth and altered metabolism. This dependency on vitamin C recycling presents a potential vulnerability that can be exploited for therapeutic intervention. By selectively disrupting the vitamin C recycling pathway in cancer cells, we aim to inhibit their growth and survival while minimizing effects on healthy cells. 
    • Approach: Our drug design strategies are grounded in the detailed structural information deciphered from the in-house solved crystal structures of human, plant and bacterial enzymes involved in vitamin C recycling; conversion of oxidized vitamin C (monodehydroascorbate; MDHA and dehydroascorbate; DHA) to its reduced form. These include human chloride intracellular channel 1 (HsCLIC1), Pennisetum glaucummonodehydroascorbate reductase (PgMDHAR), and dehydroascorbate reductase (PgDHAR), and E. coliGlutaredoxin 2 (EcGrx2). The crystals structures solved with native ligands and small molecule inhibitors help us in rational drug discovery.
    • Research Goals:
      • Enzyme inhibition: Development of potent and selective inhibitors against the enzymatic form of HsCLIC1, which is essential for maintaining cellular redox balance and supporting cancer cell growth.
      • Blocking ion channel: CLIC proteins, including HsCLIC1, also function as ion channels. By developing novel inhibitors that block the CLIC ion channel, we aim to explore an additional avenue for disrupting cancer cell function. 
    • Potential Impact: The successful development of inhibitors targeting vitamin C recycling could represent a paradigm shift in cancer therapy. By exploiting a unique metabolic dependency of cancer cells, we can potentially develop new treatment options with improved efficacy and reduced side effects. This approach could complement existing therapies or be used in combination to overcome drug resistance, a major challenge in cancer treatment.

Collaboration and Funding: Our projects address critical challenges in cardiovascular disease and cancer treatment, offering potential for transformative therapeutic breakthroughs. We actively seek collaborations with academic laboratories and industry partners to advance these promising avenues of research. These collaborations represent high-impact opportunities with the potential for significant scientific and commercial returns.

Opportunities for Post-doctoral Scientists and Students:

Our lab is at the forefront of structure-based drug discovery targeting cardiovascular disease and cancer. We offer a dynamic and collaborative research environment where postdoctoral scientists and students can gain hands-on experience in all aspects of early drug discovery, from in silico computational screening and design to preclinical validation in vitroand in vivo

Let Us Talk!

  • For inquiries on supporting post-doctoral fellowship applications, PhD lab rotation and short-term/long-term project training write to: [email protected] / [email protected]
Work-flow stages: 1) Identify potential drug candidates using virtual screening techniques and shortlist using molecular dynamics, 2) Preclinical validation in vitro: Biochemical, Biophysical and cell-based assays, 3) Target-inhibitor complex structure determination using X-ray crystallography, 4) Design of novel molecules based on structural data, 5) Custom-synthesis of molecules (outsourced) and SAR-based studies, 6) Preclinical validation in vivo: animal models.

Publications

Khan, Mohd Azeem, Irshad Mohammad, Sohom Banerjee, Akanksha Tomar, Kottayil I. Varughese, Jawahar L. Mehta, Anmol Chandele, and Arulandu Arockiasamy. “Oxidized LDL receptors: a recent update.” Current Opinion in Lipidology 34, no. 4 (2023): 147-155. DOI: 10.1097/MOL.0000000000000884.
https://doi.org/10.1097/MOL.0000000000000884

Sonkar, Kirti Shila, V. Mohan Murali Achary, Sibasis Sahoo, Malireddy K. Reddy, and Arulandu Arockiasamy. “Biochemical and structural characterization of a robust and thermostable ascorbate recycling monodehydroascorbate reductase (MDHAR) from stress adapted pearl millet.” Biochemical and Biophysical Research Communications 662 (2023): 135-141. https://doi.org/10.1016/j.bbrc.2023.04.034.

Das, Bhaba Krishna, Wajahat Ali Khan, Sreeshma Nellootil Sreekumar, Kannapiran Ponraj, V. Mohan Murali Achary, Elluri Seetharami Reddy, D. Balasubramaniam, Anmol Chandele, Malireddy K. Reddy, and Arulandu Arockiasamy. “Plant dehydroascorbate reductase moonlights as membrane integrated ion channel.” Archives of Biochemistry and Biophysics 741 (2023): 109603. https://doi.org/10.1016/j.abb.2023.109603.

Fatima, U., Balasubramaniam, D., Khan, W. A., Kandpal, M., Vadassery, J., Arockiasamy, A., & Senthil-Kumar, M. (2023). AtSWEET11 and AtSWEET12 transporters function in tandem to modulate sugar flux in plants. Plant Direct, 7(3), e481. https://doi.org/10.1002/pld3.481

Tomar, Akanksha, Sibasis Sahoo, Muthusankar Aathi, Shobhan Kuila, Mohd Azeem Khan, Guru Raj Rao Ravi, Jeyakanthan Jeyaraman, Jawahar L. Mehta, Kottayil I. Varughese, and Arulandu Arockiasamy. “Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis.” Biochemical and Biophysical Research Communications 623 (2022): 59-65. https://doi.org/10.1016/j.bbrc.2022.07.036

Das, Bhaba Krishna, Amit Kumar, Sreeshma Nellootil Sreekumar, Kannapiran Ponraj, Kaustubh Gadave, Saravanan Kumar, V. Mohan Murali Achary, Pratima Ray, Malireddy K. Reddy, and Arulandu Arockiasamy. “Comparative kinetic analysis of ascorbate (Vitamin-C) recycling dehydroascorbate reductases from plants and humans.” Biochemical and Biophysical Research Communications 591 (2022): 110-117. https://doi.org/10.1016/j.bbrc.2021.12.103.

Panchariya, Love, Wajahat Ali Khan, Shobhan Kuila, Kirtishila Sonkar, Sibasis Sahoo, Archita Ghoshal, Ankit Kumar et al. “Zinc 2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro.” Chemical Communications 57, no. 78 (2021): 10083-10086. https://doi.org/10.1039/D1CC03563K
Babu K, Arulandu A, Sankaran K. The structure of DLP12 endolysin exhibiting alternate loop conformation and comparative analysis with other endolysins. Proteins. 2018; 86: 210–217. https://doi.org/10.1002/prot.25428

Pothineni, Naga Venkata K., Sotirios K. Karathanasis, Zufeng Ding, Arockiasamy Arulandu, Kottayil I. Varughese, and Jawahar L. Mehta. “LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation.” Journal of the American College of Cardiology 69, no. 22 (2017): 2759-2768.https://doi.org/10.1016/j.jacc.2017.04.010

Krishna Das, B., Kumar, A., Maindola, P., Mahanty, S., Jain, S. K., Reddy, M. K., & Arockiasamy, A. (2016). Non-native ligands define the active site of Pennisetum glaucum (L.) R. Br dehydroascorbate reductase. Biochemical and biophysical research communications, 473(4), 1152–1157. https://doi.org/10.1016/j.bbrc.2016.04.031

Maindola, P., Raina, R., Goyal, P., Atmakuri, K., Ojha, A., Gupta, S., Christie, P. J., Iyer, L. M., Aravind, L., & Arockiasamy, A. (2014). Multiple enzymatic activities of ParB/Srx superfamily mediate sexual conflict among conjugative plasmids. Nature communications, 5, 5322. https://doi.org/10.1038/ncomms6322