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Overview

Tags

Infectious Diseases

Skin and Musculoskeletal Diseases

Endocrinology and Metabolic Disease

Small molecule drug

Chemical drugs

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Infectious Diseases	5
Endocrinology and Metabolic Disease	3
Neoplasms	3

Top 5 Drug Type	Count

Small molecule drug	11
Chemical drugs	2

Top 5 Target	Count

CALCR x ERα x TGF-β3	1

The present study aimed at identifying the genetic mutation responsible for teratozoospermic infertility in a case with coiled sperm tails. A 33-year-old infertile male was diagnosed with teratozoospermic infertility, with sperm head in coiled (HIC) tail as the most common deformity. We employed whole exome sequencing to identify the genetic cause in this case. Exome sequencing data was filtered using the following criteria: MAF (< 0.003), ALFA project (< 0.001), 1000 Genomes (< 0.003), Granthem (> 50), Polyphen-2 (> 0.70), SIFT (< 0.03), and PhyloP (> = 0) scores. Shortlisted variants were looked in the in-house 29 exomes data available with us, and the variants that affected conserved amino acid residues or led to insertion/deletion or to protein-truncation with a Combined Annotation Dependent Depletion (CADD) score ≥ 10 were shortlisted. The variants thus populated were prioritized according to their roles in spermiogenesis. The study identified a heterozygous mutation c.826C > T (Arg276Trp) in the SPEM1 gene as a potential pathogenic variant that led to teratozoospermic infertility in the case under investigation. The mutation had a minor allele frequency of 0.00008176 in the gnomAd database and was absent in the Indian Genome Variations database. This is the first human study reporting a mutation in the SPEM1 gene as a cause of coiled sperm tails.

02 Jul 2024·Journal of Biomolecular Structure and Dynamics

Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19

Article

Author: Wagh, Padmakar ; Mandal, Amit Kumar ; Baliyan, Aastha ; Prabhakar, Yenamandra S ; Velusamy, Umashankar ; Bhattacharyya, Parthasarathi ; Tadala, Raghu ; Kurpad, Anura V ; Mitra, Amrita ; Dewaker, Varun ; Krishnan, Kiran ; Debnath, Utsab

The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.

01 Jul 2024·Free Radical Biology and Medicine

iNOS regulates hematopoietic stem and progenitor cells via mitochondrial signaling and is critical for bone marrow regeneration

Article

Author: Singh, Krishna Bhan ; Singh, Divya ; Dikshit, Madhu ; Mugale, Madhav Nilakanth ; Nahiyera, Milind ; Sinha, Supriya ; Kumar, Sachin ; Kumaravelu, Jagavelu ; Sharma, Sharad ; Dhankani, Priyanka

Hematopoietic stem cells (HSCs) replenish blood cells under steady state and on demand, that exhibit therapeutic potential for Bone marrow failures and leukemia. Redox signaling plays key role in immune cells and hematopoiesis. However, the role of reactive nitrogen species in hematopoiesis remains unclear and requires further investigation. We investigated the significance of inducible nitric oxide synthase/nitric oxide (iNOS/NO) signaling in hematopoietic stem and progenitor cells (HSPCs) and hematopoiesis under steady-state and stress conditions. HSCs contain low levels of NO and iNOS under normal conditions, but these increase upon bone marrow stress. iNOS-deficient mice showed subtle changes in peripheral blood cells but significant alterations in HSPCs, including increased HSCs and multipotent progenitors. Surprisingly, iNOS-deficient mice displayed heightened susceptibility and delayed recovery of blood progeny following 5-Fluorouracil (5-FU) induced hematopoietic stress. Loss of quiescence and increased mitochondrial stress, indicated by elevated MitoSOX and MMP^hi HSCs, were observed in iNOS-deficient mice. Furthermore, pharmacological approaches to mitigate mitochondrial stress rescued 5-FU-induced HSC death. Conversely, iNOS-NO signaling was required for demand-driven mitochondrial activity and proliferation during hematopoietic recovery, as iNOS-deficient mice and NO signaling inhibitors exhibit reduced mitochondrial activity. In conclusion, our study challenges the conventional view of iNOS-derived NO as a cytotoxic molecule and highlights its intriguing role in HSPCs. Together, our findings provide insights into the crucial role of the iNOS-NO-mitochondrial axis in regulating HSPCs and hematopoiesis.

100 Deals associated with Central Drug Research Institute

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100 Translational Medicine associated with Central Drug Research Institute

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Pipeline

Pipeline Snapshot as of 07 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Discovery

4

7

Preclinical

IND Application

1

2

IND Approval

Phase 1 Clinical

1

16

Other

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

CDRI-99-373 ( CALCR x ERα x TGF-β3 )	Osteoporosis More	Phase 1
S-007-867	Thrombosis More	IND Approval
L-Ormeloxifene	Contraception More	IND Approval
S-007-1500	Fractures, Bone More	IND Application
S-011-1793	Malaria More	Preclinical