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In-Silico Development of 1, 7-Dihydrodipyrrolo [2,3-b:3’,2’-e] Pyridine -3-carboxamide Derivatives as Candidate Janus Kinase Inhibitors to Control Rheumatoid Arthritis

In-Silico Development of 1, 7-Dihydrodipyrrolo [2,3-b:3’,2’-e] Pyridine -3-carboxamide Derivatives as Candidate Janus Kinase Inhibitors to Control Rheumatoid Arthritis

Neelam Pery*, Nayab Batool Rizvi, Muhammad Imtiaz Shafiq

Institute of Biochemistry and Biotechnology, University of the Punjab, Pakistan.

Corresponding author: Neelam Pery neelam.wafa@gmail.com

ABSTRACT

Therapeutic options for rheumatoid arthritis have increased tremendously over the last two decades. The persistent monopoly of the conventional disease-modifying anti-rheumatic drugs over the drug platform has been taken over by a number of biologics including TNFα inhibitors, IL-1 inhibitors, IL-6 inhibitors, and co-stimulatory signal inhibitors with better efficacy and safety profile. However, certain factors such as lack of universal response, the need for prolonged therapy, subcutaneous or intravenous mode of administration along with high cost have rendered these unattractive. All this has paved the path for orally available small molecule kinase inhibitors and ‘Tofacitinib’, the first FDA approved Janus kinase inhibitor, invaded the market. The success of ‘Tofacitinib’ has switched on the myriad efforts for more efficacious and safe inhibitors. Here we report the in-Silico development of novel 1, 7-dihydrodipyrrolo[2,3-b:3’,2’-e]pyridine -3-carboxamide derivatives as JAK3 inhibitors with predicted efficacy more than that of Tofacitinib. Although the dipyrrolopyridine analogues have already been used for developing inhibitors for different biological conditions, the presented arrangement (1, 7-dihydrodipyrrolo[2,3-b:3’,2’-e]pyridine ) has not been explored before. Due to the linear arrangement of its rings and characteristic position of hydrogen bond donors and acceptors, it can accommodate the conformational changes of the binding cavity while maintaining interactions with the ATP binding residues. The designed inhibitors show some selectivity for JAK 1 and 3 over JAK2 offering a better safety profile against the harmful effects of JAK2 inhibition.

Novelty Statement | The work presents the identification of novel dihydrodipyrrolopyridine-3-carboxamide derivatives as novel Janus kinase inhibitors with enhanced predicted efficacy and selectivity. 1, 7-dihydrodipyrrolo[2,3-b:3’,2’-e]pyridine moiety has emerged as novel hinge binding motif with features suitable to be explored for the development of ATP competitor kinase inhibitors for different medical conditions.
 

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Punjab University Journal of Zoology

December

Vol. 35, Iss. 2, pp. 167-268

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